US8455626B2 - Aβ conformer selective anti-aβ globulomer monoclonal antibodies - Google Patents

Aβ conformer selective anti-aβ globulomer monoclonal antibodies Download PDF

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US8455626B2
US8455626B2 US11/945,124 US94512407A US8455626B2 US 8455626 B2 US8455626 B2 US 8455626B2 US 94512407 A US94512407 A US 94512407A US 8455626 B2 US8455626 B2 US 8455626B2
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antibody
antibodies
globulomer
antigen
seq
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US20090035307A1 (en
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Stefan Barghorn
Heinz Hillen
Andreas R. Striebinger
Boris Labkovsky
Ulrich Ebert
Patrick Keller
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AbbVie Deutschland GmbH and Co KG
AbbVie Inc
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Abbott Laboratories
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Priority to US13/862,865 priority patent/US9359430B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14—Specific host cells or culture conditions, e.g. components, pH or temperature
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer

Definitions

  • the subject invention relates to monoclonal antibodies that may be used in the treatment and diagnosis of Alzheimer's Disease.
  • the present invention relates to monoclonal antibodies referred to as 10F4 and 3C5 and to other monoclonal antibodies (e.g., murine, human or humanized) having similar properties thereto.
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • extra-cellular amyloid plaques these deposits consist mostly of amyloid- ⁇ -peptide filaments, and in the case of the intracellular neurofibrillary tangles (NFTs), mostly of the tau protein.
  • NFTs neurofibrillary tangles
  • the amyloid ⁇ (A ⁇ ) peptide arises from the ⁇ -amyloid precursor protein by proteolytic cleavage. This cleavage is effected by the cooperative activity of several proteases named ⁇ -, ⁇ - and ⁇ -secretase. Cleavage leads to a number of specific fragments of differing length.
  • amyloid plaques consist mostly of peptides with a length of 40 or 42 amino acids (A ⁇ 40, A ⁇ 42).
  • the dominant cleavage product is A ⁇ 40; however, A ⁇ 42 has a much stronger toxic effect.
  • Cerebral amyloid deposits and cognitive impairments very similar to those observed in Alzheimer's disease are also hallmarks of Down's syndrome (trisomy 21), which occurs at a frequency of about 1 in 800 births.
  • protofibrils and fibrils i.e., the principal components of A ⁇ plaques
  • this hypothesis was favored until recently.
  • the discovery of soluble A ⁇ forms in A ⁇ brains, which correlates better with A ⁇ symptoms than plaque load does, has led to a revised amyloid-cascade-hypothesis.
  • Active immunization with A ⁇ peptides leads to a reduction in the formation as well as to partial dissolution of existing plaques. At the same time, it leads to alleviation of cognitive defects in APP transgenic mouse models. For passive immunization with antibodies directed to A ⁇ peptides, a reduction of an A ⁇ plaque burden was also found.
  • CAA cerebral amyloid angiopathy
  • N-terminal truncated A ⁇ globulomers represent the basic structural unit of this oligomeric A ⁇ and are a very potent antigen for active immunization of rabbits and mice leading to high antibody titers (WO2004/067561).
  • the putative pathological role of N-terminally truncated A ⁇ forms in vivo has been suggested by several recent reports of their existence in A ⁇ brains (Sergeant et al., 2003, J Neurochem, 85, 1581-1591; Thal et al., 1999, J. Neuropathol. Exp Neurol, 58, 210-216).
  • neprilysin e.g. neprilysin (NEP 24.11) or insulin degrading enzyme (IDE)
  • IDE insulin degrading enzyme
  • FIG. 1 A first figure.
  • FIG. 1( a ) shows a dot blot analysis of the specificity of different anti-A ⁇ antibodies (-6E10, -3C5, 10F4).
  • the monoclonal antibodies tested here were obtained by active immunization of mice with A ⁇ (12-42) globulomer (prepared as described in Example I) followed by selection of the fused hybridoma cells (except for the commercially available 6E10, Signet, Cat. No.: 9320).
  • the individual A ⁇ forms were applied in serial dilutions and incubated with the respective monoclonal antibodies for immune reaction:
  • FIG. 1( b ) illustrates a quantitative evaluation which was done using a densitometric analysis of the intensity. For each A ⁇ form, only the dot corresponding to the lowest antigen concentration was evaluated provided that it had a relative density of greater than 20% of the relative density of the last optically unambiguously identified dot of the A ⁇ (1-42) globulomer (threshold). This threshold value was determined for every dot-blot independently. The value indicates the relationship between recognition of A ⁇ (1-42) globulomer and the respective A ⁇ form for the antibody given.
  • FIG. 2 illustrates the results of A ⁇ -peptide immunoprecipitated from Alzheimer's disease brain tissue.
  • FIG. 2( a ) represents a detailed description of the patient material that was used for analysis.
  • FIG. 2( b ) illustrates the immunoprecipitated amount of A ⁇ (1-40)-peptide and A ⁇ (1-42)-peptide as quantified by SELDI-MS analysis for the different patient and control brain samples with the antibodies 6E10, 3C5, 10F4 and the control antibody IgG2b.
  • FIG. 2( c ) illustrates the relative immunoprecipitated amount of A ⁇ (1-40)-peptide and A ⁇ (1-42)-peptide as quantified by SELDI-MS analysis for the different patient and control brain samples with the antibodies 3C5, 10F4 and the control antibody IgG2b compared to the pan-A ⁇ -antibody 6E10 in percent.
  • the total amount of A ⁇ -peptide immunoprecipitated by antibody 6E10 was set to 100%.
  • FIG. 2( d ) illustrates the immunoprecipitated amount of A ⁇ -peptide as quantified by Western blot analysis for the different patient and control brain samples with the antibodies 6E10, 3C5, 10F4 and the control antibody IgG2b.
  • FIG. 2( e ) illustrates the relative immunoprecipitated amount of A ⁇ -peptide as quantified by western blot analysis for the different patient and control brain samples with the antibodies 3C5, 10F4 and the control antibody IgG2b compared to the pan-A ⁇ -antibody 6E10 in percent.
  • the total amount of A ⁇ -peptide immunoprecipitated by antibody 6E10 was set to 100%.
  • FIG. 3( a ) shows a Coomassie stained SDS PAGE of:
  • FIG. 3( b ) shows the densitometric quantitative analysis of in vitro antibody binding to A ⁇ -fibrils.
  • FIG. 4 shows the binding of antibodies at different concentrations to transversal sections of the neocortices of Alzheimer's disease (AD) patients or old APP transgenic mice.
  • FIG. 4( a ) represents the verification of amyloid deposits by Congo Red staining as plaques in brain tissue and as cerebral amyloid angiopathy (CAA) in brain vessels in the APP transgenic mouse line Tg2576 and in an AD patient (RZ55).
  • CAA cerebral amyloid angiopathy
  • FIG. 4( b ) shows the strong staining of parenchymal deposits of A ⁇ (amyloid plaques) in an AD patient (RZ16) occurs only with 6G1 and the commercially available antibody 6E10 while 10F4 and 3C5 show considerably weaker staining. All antibodies were tested at a concentration of 0.7 ⁇ g/mL.
  • FIG. 4( c ) shows the strong staining of parenchymal deposits of A ⁇ (amyloid plaques) in TG2576 mice occurs only with 6G1 and the commercially available antibody 6E10 while 10F4 and 3C5 show considerably weaker staining. All antibodies were tested at a concentration of 0.7 ⁇ g/mL.
  • FIG. 4( d ) shows the binding of 0.7 ⁇ g/mL antibody in Tg2576 mice.
  • FIG. 4( e ) shows the binding of 0.07-0.7 ⁇ g/mL antibody in APP/L mice.
  • FIG. 4( f ) shows the binding of 0.7 ⁇ g/mL antibody in an AD patient (RZ55), and FIG.
  • FIGS. 4( g ) shows the binding of 0.07-0.7 ⁇ g/mL antibody in an AD patient (RZ16).
  • the antibodies 10F4 and 3C5 showed always significantly less staining than the commercially available antibodies 6E10 and 4G8 (p ⁇ 0.05 in post-hoc t-test after p ⁇ 0.001 in ANOVA).
  • FIG. 4( h ) shows the strong staining of vascular deposits of A ⁇ (arrows) occurs only with 6G1 and the commercially available antibody 6E10 while staining with 8F5 or 8C5 was much weaker. All antibodies were tested at a concentration of 0.7 ⁇ g/mL. A qualitatively similar situation was found in Tg2576 mice (not shown here).
  • FIGS. 5( b ), ( d ), ( f ) and ( h ) shows the relative amount of A ⁇ (1-40) and A ⁇ (1-42) peptide immunoprecipitated from Alzheimer's disease patient CSF by the antibodies 10F4, 3C5 and 8F5 compared to the amount of A ⁇ -peptide immunoprecipitated by the antibody 6E10 in percent.
  • the total amount of A ⁇ -peptide immunoprecipitated by mAb 6E10 antibody was set to 100%.
  • FIG. 5( i ) represents a detailed description of the Alzheimer's disease patient CSF material that was used for analysis in FIGS. 5( a )- 5 ( i ).
  • FIG. 6( a ) illustrates the DNA sequence (SEQ ID NO:1) of the variable heavy chain encoding the monoclonal antibody referred to herein as “3C5”.
  • FIG. 6( b ) illustrates the DNA sequence (SEQ ID NO:2) of the variable light chain encoding the monoclonal antibody referred to herein as “3C5”.
  • FIG. 6( c ) illustrates the DNA sequence (SEQ ID NO:3) of the variable heavy chain encoding the monoclonal antibody referred to herein as “10F4”.
  • FIG. 6( d ) illustrates the DNA sequence (SEQ ID NO:4) of the variable light chain encoding the monoclonal antibody referred to herein as “10F4”.
  • FIG. 7( a ) illustrates the amino acid sequence (SEQ ID NO:5) of the variable heavy chain encoding the monoclonal antibody referred to herein as “3C5”.
  • FIG. 7( b ) illustrates the amino acid sequence (SEQ ID NO:6) of the variable light chain encoding the monoclonal antibody referred to herein as “3C5”.
  • FIG. 7( c ) illustrates the amino acid sequence (SEQ ID NO:7) of the variable heavy chain encoding the monoclonal antibody referred to herein as “10F4”.
  • FIG. 7( d ) illustrates the amino acid sequence (SEQ ID NO:8) of the variable light chain encoding the monoclonal antibody referred to herein as “10F4”. (Complementarity determining regions (CDRS) are underlined in each described sequence.)
  • the present invention encompasses antibodies, directed against A ⁇ globulomers, which improve the cognitive performance of a patient in immunotherapy, while at the same time reacting only with a small portion of the entire amount of A ⁇ peptide in the brain.
  • Such properties prevent a substantial disturbance of cerebral A ⁇ balance and lead to less side effects.
  • a therapeutically questionable reduction of brain volume has been observed in the study of active immunization with A ⁇ peptides in fibrillary condition of aggregation (ELAN Corporation Plc, South San Francisco, Calif., USA and Dublin, UK) of active immunization with AN-1792 (A ⁇ (1-42) peptide in fibrillary condition of aggregation).
  • AN-1792 A ⁇ (1-42) peptide in fibrillary condition of aggregation
  • the present invention solves the above-noted side effect issues by providing A ⁇ globulomer antibodies possessing high affinity for A ⁇ globulomers. These antibodies are capable of discriminating other forms of A ⁇ peptides, particularly monomers, fibrils and sAPP ⁇ . Further, the antibodies of the present invention also discriminate against amyloid beta in the cerebrospinal fluid (CSF) by binding only to non-CSF amyloid beta. Additionally, the antibodies of the present invention (e.g., 10F4 and 3C5) bind less to A ⁇ -plaques and vascular A ⁇ compared to a known antibody (i.e., 6E10).
  • CSF cerebrospinal fluid
  • the present invention encompasses an isolated antibody having a higher affinity to A ⁇ (1-42) globulomer than to at least one amyloid beta protein selected from the group consisting of A ⁇ (1-42) peptide present in cerebrospinal fluid (CSF) and b) A ⁇ (1-40) peptide present in CSF.
  • the present invention also includes an isolated antibody having a binding affinity to A ⁇ (1-42) globulomer which is greater than the binding affinity to at least one amyloid beta protein selected from the group consisting of a) A ⁇ (1-42) monomer, b) A ⁇ (1-40) monomer, c) A ⁇ (1-42) fibril and d) soluble amyloid precursor protein-alpha (sAPP ⁇ ).
  • This antibody binds with greater affinity to amyloid beta protein present in non-CSF than to amyloid beta protein present in CSF.
  • the above-described antibodies may be, for example, murine, monoclonal, recombinant, human and/or humanized. Further, any one of more of the antibodies of the present invention may bind to at least one epitope, which is the same epitope or epitopes, to which the monoclonal antibody 10F4 (obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7808) or the monoclonal antibody 3C5 (obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7406) binds.
  • the monoclonal antibody 10F4 obtained from a hybridoma designated by American Type Culture Collection deposit number PTA-7808
  • the monoclonal antibody 3C5 obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7406
  • the present invention includes an isolated antibody comprising SEQ ID NO:5, an isolated antibody comprising SEQ ID NO:6 and an isolated antibody comprising both SEQ ID NO:5 and SEQ ID NO:6.
  • the present invention encompasses an isolated antibody comprising SEQ ID NO:7, an isolated antibody comprising SEQ ID NO:8 and an isolated antibody comprising both SEQ ID NO:7 and SEQ ID NO:8.
  • the above-described antibodies of the present invention may comprise at least one amino acid sequence selected from the group consisting of: a) the amino acid sequence of the heavy chain CDR3 and the amino acid sequence of the light chain CDR3 of monoclonal antibody (10F4) (obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7808) and b) the amino acid sequence of the heavy chain CDR3 and the amino acid sequence of the light chain CDR3 of monoclonal antibody (3C5) (obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7406).
  • the above-described antibodies of the present invention may comprise at least one amino acid sequence selected from the group consisting of: a) the amino acid sequence of the heavy chain CDR2 and the amino acid sequence of the light chain CDR2 of a monoclonal antibody (10F4) (obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7808) and b) the amino acid sequence of the heavy chain CDR2 and the amino acid sequence of the light chain CDR2 of a monoclonal antibody (3C5) (obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7406).
  • the antibodies of the present invention may comprise at least one amino acid sequence selected from the group consisting of: a) the amino acid sequence of the heavy chain CDR1 and the amino acid sequence of the light chain CDR1 of a monoclonal antibody (10F4) (obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7808) and b) the amino acid sequence of the heavy chain CDR1 and the amino acid sequence of the light chain CDR1 of a monoclonal antibody (3C5) (obtainable from a hybridoma designated by American Type Culture Collection deposit number PTA-7406).
  • the present invention also includes an isolated antibody comprising at least one CDR selected from the group consisting of amino acid sequence: a) SHYAWN (SEQ ID NO: 9); b) YIDYSGSTRYLPSLKS (SEQ ID NO: 10); c) GSGYFYGMDY (SEQ ID NO: d) HASQNINVWLS (SEQ ID NO: 12); e) KASNLHT (SEQ ID NO: 13); f) QQGQSYPYT (SEQ ID NO: 14); g) NYLIE (SEQ ID NO: 151; h) VINPGSGDTNYNENFKG (SEQ ID NO: 16); i) GVITTGFDY (SEQ ID NO: 17); j) RASGNIHNYLA (SEQ ID NO: 18); k) NAKTLAD (SEQ ID NO: 19) and 1) QHFWSSPRT (SEQ ID NO: 20).
  • CDR selected from the group consisting of amino acid sequence: a) SHYAWN (SEQ ID
  • the present invention encompasses a hybridoma designated by American Type Culture Collection deposit number PTA-7808 as well as a monoclonal antibody (10F4) obtainable from or produced by a hybridoma designated by American Type Culture Collection deposit number PTA-7808.
  • the invention also includes a hybridoma designated by American Type Culture Collection deposit number PTA-7406 as well as a monoclonal antibody (3C5) obtainable from or produced by a hybridoma designated by American Type Culture Collection deposit number PTA-7406.
  • the present invention includes an isolated nucleic acid molecule encoding the antibodies described above.
  • the nucleotide sequence of this molecule may comprise at least one sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4.
  • the present invention includes a vector comprising the isolated nucleic acid molecule as well as a host cell comprising the vector.
  • the present invention includes a method of producing an antibody, comprising culturing the host cell described above in a culture medium for a time and under conditions suitable for production of any one of the antibodies described above.
  • the antibody produced in accordance with this method is also included within the scope of the present invention.
  • the present invention includes a composition comprising any one or more of the antibodies described above.
  • This composition may further comprise a pharmaceutically acceptable carrier.
  • the present invention encompasses a monoclonal antibody comprising an amino acid sequence encoded by at least one nucleotide sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3 and SEQ ID NO:4.
  • This antibody may be selected from the group consisting of a monoclonal antibody produced by a hybridoma designated by American Type Culture Collection deposit number PTA-7406 and a monoclonal antibody produced by a hybridoma designated by American Type Culture Collection deposit number PTA-7808.
  • the antibody may comprise at least one amino acid sequence selected from the group consisting of SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7 and SEQ ID NO:8.
  • the invention also includes a method for treating or preventing an amyloidosis in a patient in need of such treatment or prevention.
  • This method comprises administering one or more of the above-described antibodies (via passive immunization) to the patient in an amount sufficient to effect treatment or prevention.
  • the amyloidosis may be, for example, Alzheimer's disease or the amyloidosis of Down's syndrome.
  • the present invention encompasses an isolated antibody which binds to at least one epitope of amyloid beta protein in the brain of a patient having amyloidosis.
  • This antibody may be produced, for example, by a hybridoma having an ATCC deposit number selected from the group consisting of PTA-7406 and PTA-7808.
  • the present invention also includes a method of diagnosing Alzheimer's Disease in a patient suspected of having this disease.
  • This method comprises the steps of isolating a biological sample (for example, a CSF sample or brain tissue sample) from the patient, contacting the biological sample with one or more of the antibodies described above for a time and under conditions sufficient for formation of antigen/antibody complexes, and detecting presence of the antigen/antibody complexes in the sample, presence of the complexes indicating a diagnosis of Alzheimer's Disease in the patient.
  • the antigen of the complex may be, for example, a globulomer.
  • the present invention encompasses another method of diagnosing Alzheimer's Disease in a patient suspected of having this disease.
  • This method comprises the steps of isolating a biological sample from the patient, contacting the biological sample with an antigen for a time and under conditions sufficient for the formation of antibody/antigen complexes, adding a conjugate to the resulting antibody/antigen complexes for a time and under conditions sufficient to allow the conjugate to bind to the bound antibody (wherein the conjugate comprises an isolated antibody of the present invention attached to a signal generating compound capable of generating a detectable signal), and detecting the presence of an antibody which may be present in the biological sample by detecting a signal generated by the signal generating compound, the signal indicating a diagnosis of Alzheimer's Disease in the patient.
  • the antigen used in the assay may be, for example, a globulomer.
  • the present invention includes an additional method of diagnosing Alzheimer's Disease in a patient suspected of having Alzheimer's Disease.
  • This method comprises the steps of isolating a biological sample from the patient, contacting the biological sample with an anti-antibody (wherein the anti-antibody is specific for one of more of the antibodies of the present invention), for a time and under conditions sufficient to allow for formation of anti-antibody/antibody complexes, the complexes containing antibody present in the biological sample, adding a conjugate to the resulting anti-antibody/antibody complexes for a time and under conditions sufficient to allow the conjugate to bind to bound antibody (wherein the conjugate comprises an antigen, which binds to a signal generating compound capable of generating a detectable signal), and detecting a signal generated by the signal generating compound, this signal indicating a diagnosis of Alzheimer's Disease in the patient.
  • the present invention includes a vaccine comprising one or more of the antibodies of the present invention and a pharmaceutically acceptable adjuvant.
  • the present invention encompasses a method of identifying compounds suitable for active immunization of a patient predicted to develop Alzheimer's Disease.
  • This method comprises the steps of exposing one or more compounds of interest to one or more of the antibodies of the present invention, for a time and under conditions sufficient for the one or more compounds to bind to the one or more antibodies and then identifying those compounds which bind to the one or more antibodies, the identified compounds to be used in active immunization in a patient predicated to develop Alzheimer's Disease.
  • the present invention includes a kit comprising one or more of the antibodies of the present invention and a conjugate comprising an antibody attached to a signal-generating compound, wherein the antibody of the conjugate is different from the one or more antibodies within the kit.
  • a package insert may also be included in the kit which describes the procedure to be utilized in carrying out the assay as well as the components of the kit.
  • the present invention also includes another kit comprising an anti-antibody to one or more antibodies of the present invention and a conjugate comprising an antigen attached to a signal-generating compound.
  • the antigen may be, for example, a globulomer.
  • a package insert may be included which describes the steps to be utilized in carrying out the assay as well as the components of the kit.
  • the antibodies of the present invention were designed from immunization with the truncated globulomer A ⁇ (12-42) as described in Example 1.
  • monoclonal antibodies 3C5 and 10F4 were generated against the truncated (12-42)-globulomer (in contrast to monoclonal antibodies 8F5 and 8C5 which have been made against the A ⁇ (1-42) globulomer).
  • This A ⁇ (12-42) globulomer was made directly from A ⁇ 12-42 peptide in contrast to the procedure described in Barghorn et al. (J. Neurochem, 95, 834-847) and in Example 3, Section 6, wherein the (12-42) globulomer was made from pre-existing 1-42-globulomer by limited proteolysis.
  • a ⁇ (12-42) globulomer variants differ in their final aggregation pattern.
  • the one made from A ⁇ (12-42) peptide shows only the intermediate globulomer forms (“oligomer A” as described in WO2004/067561) and the one made from the pre-existing A ⁇ (1-42)-globulomer is the mature globulomer (“oligomer B” as described in WO2004/067561).
  • a therapeutically questionable reduction of brain volume has been observed in the study of active immunization with A ⁇ peptides in fibrillary condition of aggregation (ELAN trial with AN1792).
  • ELAN trial with AN1792 severe side effects in form of a meningoencephalitis were observed.
  • the present invention solves this problem by providing globulomer-specific antibodies possessing high affinity for A ⁇ globulomers.
  • antibodies are capable of discriminating other forms of A ⁇ peptides, particularly monomers and fibrils. Further, these antibodies do not bind (or bind with a lower affinity compared to commercially available antibodies (such as 6E10) (Signet Cat. no.: 9320)) to amyloid beta in cerebral spinal fluid. Consequently, the present invention relates to an antibody having a binding affinity to A ⁇ globulomer
  • a ⁇ (X-Y) refers to the amino acid sequence from amino acid position X to amino acid position Y of the human amyloid ⁇ protein including both X and Y, in particular to the amino acid sequence from amino acid position X to amino acid position Y of the amino acid sequence DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV IAT (SEQ ID NO: 21) (corresponding to amino acid positions 1 to 43) or any of its naturally occurring variants, in particular those with at least one mutation selected from the group consisting of A2T, H6R, D7N, A21G (“Flemish”), E22G (“Arctic”), E22Q (“Dutch”), E22K (“Italian”), D23N (“Iowa”), A42T and A42V wherein the numbers are relative to the start of the A ⁇ peptide, including both position X and position Y or a sequence with up to three additional amino acid substitutions, none of which may prevent globin.
  • a ⁇ (1-42) herein refers to the amino acid sequence from amino acid position 1 to amino acid position 42 of the human amyloid ⁇ protein including both 1 and 42, in particular to the amino acid sequence DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV IA (SEQ ID NO: 22) or any of its naturally occurring variants, in particular those with at least one mutation selected from the group consisting of A2T, H6R, D7N, A21G (“Flemish”), E22G (“Arctic”), E22Q (“Dutch”), E22K (“Italian”), D23N (“Iowa”), A42T and A42V wherein the numbers are relative to the start of the AP peptide, including both 1 and 42 or a sequence with up to three additional amino acid substitutions none of which may prevent globulomer formation, preferably with no additional amino acid substitutions in the portion from amino acid 20 to amino acid 42.
  • a ⁇ (1-40) here refers to the amino acid sequence from amino acid position I to amino acid position 40 of the human amyloid ⁇ protein including both 1 and 40, in particular to the amino acid sequence DAEFRHDSGY EVHHQKLVFF AEDVGSNKGA IIGLMVGGVV (SEQ ID NO: 231 or any of its naturally occurring variants, in particular those with at least one mutation selected from the group consisting of A2T, H6R, D7N, A21G (“Flemish”), E22G (“Arctic”), E22Q (“Dutch”), E22K (“Italian”), and D23N (“Iowa”) wherein the numbers are relative to the start of the A ⁇ peptide, including both 1 and 40 or a sequence with up to three additional amino acid substitutions none of which may prevent globulomer formation, preferably with no additional amino acid substitutions in the portion from amino acid 20 to amino acid 40.
  • a ⁇ (12-42) here refers to the amino acid sequence from amino acid position 12 to amino acid position 42 of the human amyloid ⁇ protein including both 12 and 42, in particular to the amino acid sequence VHHQKLVFF AEDVGSNKGA IIGLMVGGVV IA (SEQ ID NO: 24) or any of its naturally occurring variants, in particular, those with at least one mutation selected from the group consisting of A21G (“Flemish”), E22G (“Arctic”), E22Q (“Dutch”), E22K (“Italian”), D23N (“Iowa”), A42T and A42V wherein the numbers are relative to the start of the AP peptide, including both 12 and 42 or a sequence with up to three additional amino acid substitutions none of which may prevent globulomer formation, preferably with no additional amino acid substitutions in the portion from amino acid 20 to amino acid 42.
  • a ⁇ (20-42) herein refers to the amino acid sequence from amino acid position 20 to amino acid position 42 of the human amyloid ⁇ protein including both 20 and 42, in particular, to the amino acid sequence F AEDVGSNKGA IIGLMVGGVV IA (SEQ ID NO: 25) or any of its naturally occurring variants, in particular those with at least one mutation selected from the group consisting of A21G (“Flemish”), E22G (“Arctic”), E22Q (“Dutch”), E22K (“Italian”), D23N (“Iowa”), A42T and A42V wherein the numbers are relative to the start of the A ⁇ peptide, including both 20 and 42 or a sequence with up to three additional amino acid substitutions none of which may prevent globulomer formation, preferably without any additional amino acid substitutions.
  • a ⁇ (X-Y) globulomer refers to a soluble, globular, non-covalent association of A ⁇ (X-Y) peptides as defined above, possessing homogeneity and distinct physical characteristics.
  • the A ⁇ (X-Y) globulomers are stable, non-fibrillar, oligomeric assemblies of A ⁇ (X-Y) peptides which are obtainable by incubation with anionic detergents. In contrast to monomers and fibrils, these globulomers are characterized by defined assembly numbers of subunits (e.g.
  • the globulomers have a 3-dimensional globular type structure (“molten globule”, see Barghorn et al., 2005, J Neurochem, 95, 834-847). They may be further characterized by one or more of the following features:
  • truncated forms of these globulomers maintain the 3-dimensional core structure of said globulomers with a better accessibility of the core epitope A ⁇ (20-Y) in its globulomer conformation.
  • the term “A ⁇ (X-Y) globulomer” herein refers, in particular, to a product which is obtainable by a process as described, for example, in Example I presented below. (See also WO 04/067561.) Such a process may be used to obtain A ⁇ (1-42) globulomers, A ⁇ (12-42) globulomers, and A ⁇ (20-42) globulomers.
  • the globulomer shows affinity to neuronal cells.
  • the globulomer also exhibits neuromodulating effects.
  • the globulomer consists of 11 to 16, and most preferably, of 12 to 14 A ⁇ (X-Y) peptides.
  • the term A ⁇ (X-Y) globulomer herein refers to a globulomer consisting essentially of A ⁇ (X-Y) subunits, where it is preferred if on average at least 11 of 12 subunits are of the A ⁇ (X-Y) type, more preferred if less than 10% of the globulomers comprise any non-A ⁇ (X-Y) peptides, and most preferred if the content of non-A ⁇ (X-Y) peptides is below the detection threshold.
  • a ⁇ (1-42) globulomer herein refers to a globulomer consisting essentially of A ⁇ (1-42) units as defined above; the term “A ⁇ (12-42) globulomer” herein refers to a globulomer consisting essentially of A ⁇ (12-42) units as defined above; and the term “A ⁇ (20-42) globulomer” herein refers to a globulomer consisting essentially of A ⁇ (20-42) units as defined above.
  • cross-linked A ⁇ (X-Y) globulomer refers to a molecule obtainable from an A ⁇ (X-Y) globulomer as described above by cross-linking, preferably chemically cross-linking, more preferably, aldehyde cross-linking, most preferably, glutardialdehyde cross-linking of the constituent units of the globulomer.
  • a cross-linked globulomer is essentially a globulomer in which the units are at least partially joined by covalent bonds, rather than being held together by non-covalent interactions only.
  • a cross-linked A ⁇ (1-42) globulomer is, in particular, a cross-linked A ⁇ (1-42) oligomer.
  • a ⁇ (X-Y) globulomer derivative refers, in particular, to a globulomer that is labelled by being covalently linked to a group that facilitates detection, preferably, a fluorophore, e.g., fluorescein isothiocyanate, phycoerythrin, Aequorea victoria fluorescent protein, Dictyosoma fluorescent protein or any combination or fluorescence-active derivative thereof; a chromophore; a chemoluminophore, e.g., luciferase, preferably Photinus pyralis luciferase, Vibrio fischeri luciferase, or any combination or chemoluminescence-active derivative thereof; an enzymatically active group, e.g., peroxidase, e.g., horseradish peroxidase, or any enzymatically active derivative thereof; an electron-dense group,
  • a globulomer derivative is a molecule obtainable from a globulomer by a labelling and/or flagging reaction.
  • a ⁇ (X-Y) monomer derivative herein refers, in particular, to an A ⁇ monomer that is labelled or flagged as described for the globulomer.
  • greater affinity refers to a degree of interaction where the equilibrium between unbound antibody and unbound globulomer on the one hand and antibody-globulomer complex on the other is further in favor of the antibody-globulomer complex.
  • small affinity refers to a degree of interaction where the equilibrium between unbound antibody and unbound globulomer on the one hand and antibody-globulomer complex on the other is further in favour of the unbound antibody and unbound globulomer.
  • greater affinity is synonymous with the term “higher affinity” and term “smaller affinity” is synonymous with the term “lower affinity”.
  • a ⁇ (X-Y) monomer herein refers to the isolated form of the A ⁇ (X-Y) peptide, preferably, a form of the A ⁇ (X-Y) peptide which is not engaged in essentially non-covalent interactions with other A ⁇ peptides.
  • the A ⁇ (X-Y) monomer is usually provided in the form of an aqueous solution.
  • the aqueous monomer solution contains 0.05% to 0.2%, more preferably, about 0.1% NH 4 OH.
  • the aqueous monomer solution contains 0.05% to 0.2%, more preferably, about 0.1% NaOH.
  • fibril refers to a molecular structure that comprises assemblies of non-covalently associated, individual A ⁇ (X-Y) peptides, which show fibrillary structure in the electron microscope, which bind Congo red and then exhibit birefringence under polarized light and whose X-ray diffraction pattern is a cross- ⁇ structure.
  • a fibril is a molecular structure obtainable by a process that comprises the self-induced polymeric aggregation of a suitable A ⁇ peptide in the absence of detergents, e.g., in 0.1 M HCl, leading to the formation of aggregates of more than 24, preferably more than 100 units. This process is well known in the art.
  • a ⁇ (X-Y) fibrils are used in the form of an aqueous solution.
  • the aqueous fibril solution is made by dissolving the A ⁇ peptide in 0.1% NH 4 OH, diluting it 1:4 with 20 mM NaH 2 PO 4 , 140 mM NaCl, pH 7.4, followed by readjusting the pH to 7.4, incubating the solution at 37° C. for 20 h, followed by centrifugation at 10000 g for 10 min and resuspension in 20 mM NaH 2 PO 4 , 140 mM NaCl, pH 7.4.
  • a ⁇ (X-Y) fibril herein refers to a fibril consisting essentially of A ⁇ (X-Y) subunits, where it is preferred if on average at least 90% of the subunits are of the A ⁇ (X-Y) type, more preferred, if at least 98% of the subunits are of the A ⁇ (X-Y) type and, most preferred, if the content of non-A ⁇ (X-Y) peptides is below the detection threshold.
  • the present invention also relates to antibodies having a similar binding profile to that of any one of said monoclonal antibodies, 10F4 and 3C5.
  • Antibodies having a binding profile similar to that of any one of said monoclonal antibodies include antibodies which bind to the same epitope as monoclonal antibody 10F4 and 3C5.
  • the present invention also relates to antibodies which are capable of competing with at least one, preferably all, antibodies selected from the group consisting of 10F4 and 3C5.
  • the term “competing antibodies” herein refers to any number of antibodies targeting the same molecular or stably but non-covalently linked supermolecular entity, preferably, the same molecule, wherein at least one is capable of specifically reducing the measurable binding of another, preferably, by sterically hampering the other's access to its target epitope or by inducing and/or stabilizing a conformation in the target entity that reduces the target's affinity for the other antibody, more preferably, by directly blocking access to the other's target epitope by binding to an epitope in sufficiently close vicinity of the former, overlapping with the former or identical to the former, most preferably, overlapping or identical, in particular identical.
  • Two epitopes are said to be “overlapping” if they share part of their chemical structures, preferably their amino acid sequences, and to be “identical” if their chemical structures, preferably their amino acid sequences, are identical.
  • the present invention also relates to antibodies whose target epitopes are overlapping with, preferably identical to, the target epitope of at least one of the antibodies selected from the group consisting of 10F4 and 3C5.
  • Antibodies having a similar binding profile to that of any one of said monoclonal antibodies 10F4 and 3C5 thus further include antibodies which comprise at least a portion of the antigen-binding moiety of any one of said monoclonal antibodies.
  • said portion comprises at least one complementary determining region (CDR) of any one of said monoclonal antibodies.
  • CDR complementary determining region
  • the present invention relates to antibodies comprising the amino acid sequence of the heavy chain CDR3 and/or the amino acid sequence of the light chain CDR3 of monoclonal antibody 10F4 or 3C5, respectively.
  • Specific examples of such antibodies include those which also comprise the amino acid sequence of the heavy chain CDR2 and/or the amino acid sequence of the light chain CDR2 of monoclonal antibody 10F4 or 3C5, respectively.
  • such antibodies include those which also comprise the amino acid sequence of the heavy chain CDR1 and/or the amino acid sequence of the light chain CDR1 of monoclonal antibody 10F4 or 3C5, respectively.
  • the present invention thus relates to antibodies comprising a heavy chain wherein the CDR3, CDR2 and/or CDR1 domain comprises the amino acid sequence of the heavy chain CDR3, CDR2 and/or CDR1 of monoclonal antibody 10F4 or 3C5.
  • the present invention thus relates to antibodies comprising a light chain wherein the CDR3, CDR2 and/or CDR1 domain comprises the amino acid sequence of the light chain CDR3, CDR2 and/or CDR1, respectively, of monoclonal antibody 10F4 or 3C5.
  • the antibody of the invention comprises at least two variable domain CDR sets. More preferably, the two variable domain CDR sets are selected from the group consisting of: VH 10F4 CDR Set & VL 10F4 CDR Set; VH 3C5 CDR Set & VL 3C5 CDR Set (see FIGS. 7 a - 7 d ).
  • the antibody disclosed above further comprises a human acceptor framework.
  • the antibody is a CDR grafted antibody.
  • the CDR grafted antibody comprises one or more of the CDRs disclosed above.
  • the CDR grafted antibody comprises a human acceptor framework.
  • the antibody is a humanized antibody.
  • the humanized antibody comprises one or more of the CDRs disclosed above. More preferably, the humanized antibody comprises three or more of the CDRs disclosed above. Most preferably, the humanized antibody comprises six CDRs disclosed above.
  • the CDRs are incorporated into a human antibody variable domain of a human acceptor framework.
  • the human antibody variable domain is a consensus human variable domain.
  • the human acceptor framework comprises at least one framework region amino acid substitution at a key residue, wherein the key residue is selected from the group consisting of a residue adjacent to a CDR; a glycosylation site residue; a rare residue; a residue capable of interacting with a CDR; a canonical residue; a contact residue between heavy chain variable region and light chain variable region; a residue within a Vernier zone; and a residue in a region that overlaps between a Chothia-defined variable heavy chain CDR1 and a Kabat-defined first heavy chain framework.
  • the human acceptor framework human acceptor framework comprises at least one framework region amino acid substitution, wherein the amino acid sequence of the framework is at least 65% identical to the sequence of said human acceptor framework and comprises at least 70 amino acid residues identical to said human acceptor framework.
  • the present invention relates to antibodies comprising both the heavy and light chain as defined above.
  • the antibody comprises at least one variable domain as described above. More preferably, the antibody comprises two variable domains as described above, wherein said two variable domains have amino acid sequences as noted in FIG. 7 .
  • the antibodies of the present invention comprise a heavy chain constant region selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgD, IgE and human IgG1Ala234 Ala235 mutant constant regions.
  • the antibodies comprise a human constant region.
  • Antibodies comprising an IgG1 heavy chain constant region are preferred.
  • the antibody is glycosylated.
  • the glycosylation pattern is a human glycosylation pattern or a glycosylation pattern produced by any one of the eukaryotic cells disclosed herein, in particular CHO cells.
  • the present invention also relates to an antigen-binding moiety of an antibody of the present invention.
  • antigen-binding moieties include, but are not limited to, Fab fragments, F(ab′) 2 fragments and single chain Fv fragments of the antibody. Further antigen-binding moieties are Fab′ fragments, Fv fragments, and disulfide linked Fv fragments.
  • the invention also provides an isolated nucleic acid encoding any one of the antibodies disclosed herein.
  • a further embodiment provides a vector comprising the isolated nucleic acid disclosed herein.
  • the vector may in particular be selected from the group consisting of pcDNA; pTT (Durocher et al., Nucleic Acids Research 2002, Vol 30, No. 2); pTT3 (pTT with additional multiple cloning site; pEFBOS (Mizushima, S. and Nagata, S., (1990) Nucleic acids Research Vol 18, No. 17); pBV; pJV; and pBJ.
  • a host cell is transformed with the vector disclosed herein.
  • the host cell is a prokaryotic cell. More preferably, the host cell is E. coli .
  • the host cell is an eukaryotic cell.
  • the eukaryotic cell is selected from the group consisting of a protist cell, an animal cell, a plant cell and a fungal cell. More preferably, the host cell is a mammalian cell including, but not limited to, CHO and COS; or a fungal cell such as Saccharomyces cerevisiae ; or an insect cell such as Sf9.
  • Another aspect of the invention provides a method of producing an antibody of the invention, comprising culturing any one of the host cells or a hybridoma disclosed herein in a culture medium under conditions suitable to produce the antibody.
  • Another embodiment provides an antibody that is obtainable by the method disclosed herein.
  • Antibodies of the present invention can be obtained in a manner known per se. B lymphocytes which, in totality, contain an antibody repertoire composed of hundreds of billions of different antibody specificities are a part of the mammalian immune system.
  • a normal immune response to a particular antigen means selection of one or more antibodies of said repertoire which specifically bind to said antigen, and the success of an immune response is based at least partially on the ability of said antibodies to specifically recognize (and ultimately to eliminate) the stimulating antigen and to ignore other molecules in the environment of said antibodies.
  • the usefulness of antibodies which specifically recognize one particular target antigen has led to the development of monoclonal antibody technology.
  • Standardized hybridoma technology now allows the production of antibodies with a single specificity for an antigen of interest. More recently, recombinant antibody techniques such as in-vitro screening of antibody libraries have been developed. These techniques likewise allow antibodies having a single specificity for an antigen of interest to be produced.
  • the antigen of interest may be allowed to act on the antibody repertoire either in vivo or in vitro.
  • the antigen is allowed to act on the repertoire by immunizing an animal in vivo with said antigen.
  • This in-vivo approach may furthermore comprise establishing from the lymphocytes of an animal a number of hybridomas and selecting a particular hybridoma which secretes an antibody specifically binding to said antigen.
  • the animal to be immunized may be, for example, a mouse, rat, rabbit, chicken, camelid or sheep or may be a transgenic version of any of the animals mentioned above, for example, a transgenic mouse with human immunoglobulin genes, which produces human antibodies after an antigenic stimulus.
  • mice with severe combined immunodeficiency which have been reconstituted with human peripheral mononuclear blood cells (chimeric hu-PBMC SCID mice) or with lymphoid cells or precursors thereof, as well as mice which have been treated with a lethal total body irradiation, then protected against radiation with bone marrow cells from a mouse with severe combined immunodeficiency (SCID) and subsequently transplanted with functional human lymphocytes (the “Trimera” system).
  • Another type of an animal to be immunized is an animal (e.g., a mouse) in whose genome an endogenous gene encoding the antigen of interest has been switched off (knocked out), for example, by homologous recombination, so that after immunization with the antigen, said animal recognizes said antigen as foreign.
  • the polyclonal or monoclonal antibodies produced by this method are characterized and selected by using known screening methods which include, but are not limited to, ELISA and dot blot techniques.
  • the antigen is allowed to act on the antibody repertoire in vitro by screening a recombinant antibody library with said antigen.
  • the recombinant antibody library may be expressed, for example, on the surface of bacteriophages or on the surface of yeast cells or on the surface of bacterial cells.
  • the recombinant antibody library is an ScFv library or an Fab library, for example.
  • antibody libraries are expressed as RNA-protein fusions.
  • the antigen may be allowed to act on the antibody repertoire by immunizing an animal in vivo with said antigen and then screening in vitro with said antigen a recombinant antibody library prepared from lymphoid cells of said animal or a single domain antibody library (e.g., containing heavy and/or light chains).
  • the antigen is allowed to act on the antibody repertoire by immunizing an animal in vivo with said antigen and then subjecting a recombinant antibody library or single domain library produced from lymphoid cells of said animal to affinity maturation.
  • the antigen is allowed to act on the antibody repertoire by immunizing an animal in vivo with said antigen, then selecting individual antibody-producing cells secreting an antibody of interest and obtaining from said selected cells cDNAs for the variable region of the heavy and light chains (e.g., by means of PCR) and expressing said variable regions of the heavy and light chains in mammalian host cells in vitro (this being referred to as selected lymphocyte antibody method or SLAM), thereby being able to further select and manipulate the selected antibody gene sequences.
  • monoclonal antibodies may be selected by expression cloning by expressing the antibody genes for the heavy and light chains in mammalian cells and selecting those mammalian cells which secrete an antibody having the desired binding affinity.
  • the methods of the invention for producing antibodies can be used to produce various types of antibodies. These include monoclonal, in particular recombinant antibodies, especially essentially human antibodies, chimeric antibodies, humanized antibodies and CDR graft antibodies, and also antigen-binding moieties thereof.
  • the present invention further relates to a hybridoma that is capable of producing (secreting) a monoclonal antibody of the present invention.
  • Hybridomas of the present invention include those designated by an American Type Culture Collection deposit number selected from the group consisting of PTA-7808 and PTA-7406 and those producing monoclonal antibodies 10F4 and 3C5.
  • the antibodies of the present invention may also be reactive with, i.e., bind to, A ⁇ forms other than the A ⁇ globulomers described herein. These antigens may or may not be oligomeric or globulomeric. Thus, the antigens to which the antibodies of the present invention bind include any A ⁇ form that comprises the globulomer epitope with which the antibodies of the present invention are reactive.
  • Such A ⁇ forms include truncated and non-truncated A ⁇ (X-Y) forms (with X and Y being defined as above), such as A ⁇ (20-42), A ⁇ (20-40), A ⁇ (12-42), A ⁇ (12-40), A ⁇ (1-42), and A ⁇ (1-40) forms, provided that said forms comprise the globulomer epitope.
  • the present invention also relates to a composition comprising an antibody of the invention or an antigen-binding moiety thereof, as defined above.
  • said composition is a pharmaceutical composition which comprises the antibody of the invention or the antigen-binding moiety and a pharmaceutical acceptable carrier.
  • the antibody of the invention or the antigen-binding moiety, as defined above, is preferably capable of neutralizing, both in vitro and in vivo, the activity of A ⁇ globulomer or a derivative thereof to which it binds.
  • Said antibody or antigen-binding moiety may therefore be used for inhibiting the activity of said globulomer or derivative thereof, for example, in a preparation containing said globulomer or derivative thereof or in human individuals or other mammals in which said globulomer or derivative thereof is present.
  • the invention relates to a method of inhibiting the activity of said globulomer or derivative thereof which method comprises allowing an antibody of the invention or an antigen-binding moiety thereof to act on a globulomer or derivative thereof so as to inhibit the activity of said globulomer or derivative thereof.
  • Said activity may be inhibited in vitro, for example.
  • the antibody of the invention or the antigen-binding moiety may be added to a preparation such as a sample derived from a subject or a cell culture which contains or is suspected to contain said globulomer or derivative thereof, in order to inhibit the activity of said globulomer or derivative thereof in said sample.
  • the activity of the globulomer or derivative thereof may be inhibited in an individual in vivo.
  • the present invention further relates to the use of an antibody or an antigen-binding moiety as defined above for preparing a pharmaceutical composition for treating or preventing an amyloidosis, in particular, an amyloidosis selected from the group consisting of Alzheimer's disease and the amyloidosis of Down's syndrome.
  • One aspect of said use of the invention is therefore a method of treating or preventing an amyloidosis, in particular, Alzheimer's disease or the amyloidosis of Down's syndrome, in a subject in need thereof, which comprises administering an antibody or an antigen-binding moiety as defined above to the subject.
  • said antibody or antigen-binding moiety for treating and especially preventing the amyloidosis, in particular, Alzheimer's disease or the amyloidosis of Down's syndrome is in particular for passive immunization. Accordingly, in the method of treating or preventing an amyloidosis, in particular Alzheimer's disease or the amyloidosis of Down's syndrome, in a subject in need thereof one purpose of administering the antibody or antigen-binding moiety to the subject is passively immunizing the subject against the amyloidosis, in particular, Alzheimer's disease or the amyloidosis of Down's syndrome.
  • the antibody of the invention or the antigen-binding moiety as defined above is preferably capable of detecting, both in vitro and in vivo, an A ⁇ globulomer or derivative thereof to which it binds.
  • Said antibody or the antigen-binding moiety may therefore be used for detecting said globulomer or derivative thereof, for example, in a preparation containing said globulomer or derivative thereof or in human individuals or other mammals in which said globulomer or derivatives thereof is present.
  • the invention relates to a method of detecting said globulomer or derivative thereof, which method comprises allowing an antibody of the invention or an antigen-binding moiety thereof to act on a globulomer or derivative thereof so as to bind to said globulomer or derivative thereof (and thereby preferably forming a complex comprising the antibody or antigen-binding moiety thereof and the globulomer or derivative thereof).
  • the globulomer may be detected in vitro, for example.
  • the antibody of the invention or the antigen-binding moiety may be added to a preparation, for instance, a sample derived from a subject or a cell culture which contains or is suspected to contain said globulomer or derivative thereof, in order to detect said globulomer or derivative thereof in said preparation.
  • the globulomer or derivative thereof may be detected in an individual in vivo.
  • the present invention further relates to the use of an antibody or an antigen-binding moiety as defined above for preparing a composition for diagnosing an amyloidosis, in particular Alzheimer's disease or the amyloidosis of Down's syndrome.
  • One aspect of said use of the invention is a method of diagnosing an amyloidosis, in particular, Alzheimer's disease or the amyloidosis of Down's syndrome, in a subject suspected of having the amyloidosis, in particular Alzheimer's disease or the amyloidosis of Down's syndrome, which comprises administering to the subject an antibody or an antigen-binding moiety as defined above and detecting the formation of a complex comprising the antibody or the antigen-binding moiety with the antigen, the presence of the complex indicating the amyloidosis, in particular Alzheimer's disease or the amyloidosis of Down's syndrome, in the subject.
  • a second aspect of said use of the invention is a method of diagnosing an amyloidosis, in particular, Alzheimer's disease or the amyloidosis of Down's syndrome, in a subject suspect of having the amyloidosis, in particular, Alzheimer's disease or the amyloidosis of Down's syndrome, which comprises providing a sample from the subject, contacting the sample with an antibody or an antigen-binding moiety (as defined) above and detecting the formation of a complex comprising the antibody or the antigen-binding moiety with the antigen, the presence of the complex indicating the amyloidosis, in particular, Alzheimer's disease or the amyloidosis of Down's syndrome, in the subject.
  • an antibody or an antigen-binding moiety as defined
  • the binding affinities of the antibodies of the invention may be evaluated by using standardized in-vitro immunoassays such as ELISA, dot blot or BIAcore analyses (Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.).
  • in-vitro immunoassays such as ELISA, dot blot or BIAcore analyses
  • the affinities defined herein refer to the values obtained by performing a dot blot and evaluating it by densitometry.
  • determining the binding affinity by dot blot comprises the following: a certain amount of the antigen (e.g.
  • the relative affinity of two different antibodies to one target, or of one antibody to two different targets is here defined as the relation of the respective amounts of target-bound antibody observed with the two antibody-target combinations under otherwise identical dot blot conditions.
  • the dot blot approach will determine an antibody's affinity to a given target in the latter's natural conformation; unlike the ELISA approach, the dot blot approach does not suffer from differences in the affinities between different targets and the matrix, thereby allowing for more precise comparisons between different targets.
  • K d is intended to refer to the dissociation constant of a particular antibody-antigen interaction as is known in the art.
  • the antibodies of the present invention are preferably isolated antibodies.
  • An isolated antibody means an antibody having the binding affinities as described above and which is essentially free of other antibodies having different binding affinities.
  • the term “essentially free” here refers to an antibody preparation in which at least 95% of the antibodies, preferably at least 98% of the antibodies and more preferably at least 99% of the antibodies have the desired binding affinity.
  • an isolated antibody may be substantially free of other cellular material and/or chemicals.
  • the isolated antibodies of the present invention include monoclonal antibodies.
  • a “monoclonal antibody” as used herein is intended to refer to a preparation of antibody molecules, antibodies which share a common heavy chain and common light chain amino acid sequence, in contrast with “polyclonal” antibody preparations which contain a mixture of antibodies of different amino acid sequence.
  • Monoclonal antibodies can be generated by several novel technologies like phage, bacteria, yeast or ribosomal display, as well as by classical methods exemplified by hybridoma-derived antibodies (e.g., an antibody secreted by a hybridoma prepared by hybridoma technology, such as the standard Kohler and Milstein hybridoma methodology ((1975) Nature 256:495-497).
  • a non-hybridoma-derived antibody with uniform sequence is still referred to as a monoclonal antibody herein although it may have been obtained by non-classical methodologies, and the term “monoclonal” is not restricted to hybridoma-derived antibodies but used to refer to all antibodies derived from one nucleic acid clone.
  • the monoclonal antibodies of the present invention include recombinant antibodies.
  • the term “recombinant” as used herein refers to any artificial combination of two otherwise separated segments of sequence, e.g., by chemical synthesis or by the manipulation of isolated segments of nucleic acids by genetic engineering techniques.
  • recombinant antibody refers to antibodies which are produced, expressed, generated or isolated by recombinant means, such as antibodies which are expressed using a recombinant expression vector transfected into a host cell; antibodies isolated from a recombinant combinatorial antibody library; antibodies isolated from an animal (e.g. a mouse) which is transgenic due to human immunoglobulin genes (see, for example, Taylor, L. D., et al. (1992) Nucl. Acids Res. 20:6287-6295); or antibodies which are produced, expressed, generated or isolated in any other way in which particular immunoglobulin gene sequences (such as human immunoglobulin gene sequences) are assembled with other DNA sequences.
  • Recombinant antibodies include, for example, chimeric, CDR graft and humanized antibodies.
  • the person skilled in the art will be aware that expression of a conventional hybridoma-derived monoclonal antibody in a heterologous system will require the generation of a recombinant antibody even if the amino acid sequence of the resulting antibody protein is not changed or intended to be changed.
  • the antibody is a humanized antibody.
  • the antibody may comprise an amino acid sequence derived entirely from a single species, such as a human antibody or a mouse antibody.
  • the antibody may be a chimeric antibody or a CDR graft antibody or another form of a humanized antibody.
  • antibody is intended to refer to immunoglobulin molecules consisting of 4 polypeptide chains, two heavy (H) chains and two light (L) chains.
  • the chains are usually linked to one another via disulfide bonds.
  • Each heavy chain is composed of a variable region of said heavy chain (abbreviated here as HCVR or VH) and a constant region of said heavy chain.
  • the heavy chain constant region consists of three domains CH1, CH2 and CH3.
  • Each light chain is composed of a variable region of said light chain (abbreviated here as LCVR or VL) and a constant region of said light chain.
  • the light chain constant region consists of a CL domain.
  • VH and VL regions may be further divided into hypervariable regions referred to as complementarity-determining regions (CDRs) and interspersed with conserved regions referred to as framework regions (FR).
  • CDRs complementarity-determining regions
  • FR framework regions
  • Each VH and VL region thus consists of three CDRs and four FRs which are arranged from the N terminus to the C terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. This structure is well known to those skilled in the art.
  • antibody moiety refers to one or more fragments of an antibody of the invention, said fragments) still having the binding affinities as defined above. Fragments of a complete antibody have been shown to be able to carry out the antigen-binding function of an antibody.
  • binding fragments include (i) an Fab fragment, i.e. a monovalent fragment composed of the VL, VH, CL and CH1 domains; (ii) an F(ab′) 2 fragment, i.e.
  • a bivalent fragment comprising two Fab fragments linked to one another in the hinge region via a disulfide bridge; (iii) an Fd fragment composed of the VH and CH1 domains; (iv) an Fv fragment composed of the FL and VH domains of a single arm of an antibody; (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546) consisting of a VH domain or of VH, CH1, CH2, DH3, or VH, CH2, CH3; and (vi) an isolated complementarity-determining region (CDR).
  • CDR complementarity-determining region
  • the two domains of the Fv fragment namely VL and VH
  • a synthetic linker e.g. a poly-G 4 S amino acid sequence
  • recombinant methods making it possible to prepare them as a single protein chain in which the VL and VH regions combine in order to form monovalent molecules
  • Single chain Fv Single chain Fv
  • the term “antigen-binding moiety” of an antibody is also intended to comprise such single chain antibodies.
  • Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker which is too short for the two domains being able to combine on the same chain, thereby forcing said domains to pair with complementary domains of a different chain and to form two antigen-binding sites (see, for example, Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1121-1123).
  • An immunoglobulin constant domain refers to a heavy or light chain constant domain. Human IgG heavy chain and light chain constant domain amino acid sequences are known in the art.
  • an antibody of the present invention or antigen-binding moiety thereof may be part of a larger immunoadhesion molecule formed by covalent or noncovalent association of said antibody or antibody moiety with one or more further proteins or peptides.
  • immunoadhesion molecules are the use of the streptavidin core region in order to prepare a tetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) Human Antibodies and Hybridomas 6:93-101) and the use of a cystein residue, a marker peptide and a C-terminal polyhistidinyl, e.g.
  • human antibody refers to antibodies whose variable and constant regions correspond to or are derived from immunoglobulin sequences of the human germ line, as described, for example, by Kabat et al. (see Kabat, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition , U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • the human antibodies of the invention may contain amino acid residues not encoded by human germ line immunoglobulin sequences (for example mutations which have been introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs, and in particular in CDR3.
  • Recombinant human antibodies of the invention have variable regions and may also contain constant regions derived from immunoglobulin sequences of the human germ line (see Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition , U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • recombinant human antibodies are subjected to in-vitro mutagenesis (or to a somatic in-vivo mutagenesis, if an animal is used which is transgenic due to human Ig sequences) so that the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences which although related to or derived from VH and VL sequences of the human germ line, do not naturally exist in vivo within the human antibody germ line repertoire.
  • recombinant antibodies of this kind are the result of selective mutagenesis or back mutation or of both.
  • mutagenesis leads to an affinity to the target which is greater, and/or an affinity to non-target structures which is smaller than that of the parent antibody.
  • chimeric antibody refers to antibodies which contain sequences for the variable region of the heavy and light chains from one species and constant region sequences from another species, such as antibodies having murine heavy and light chain variable regions linked to human constant regions.
  • CDR-grafted antibody refers to antibodies which comprise heavy and light chain variable region sequences from one species but in which the sequences of one or more of the CDR regions of VH and/or VL are replaced with CDR sequences of another species, such as antibodies having murine heavy and light chain variable regions in which one or more of the murine CDRs (e.g., CDR3) has been replaced with human CDR sequences.
  • humanized antibody refers to antibodies which contain sequences of the variable region of heavy and light chains from a nonhuman species (e.g. mouse, rat, rabbit, chicken, camelid, sheep or goat) but in which at least one part of the VH and/or VL sequence has been altered in order to be more “human-like”, i.e. to be more similar to variable sequences of the human germ line.
  • a humanized antibody is a CDR graft antibody in which human CDR sequences have been inserted into nonhuman VH and VL sequences to replace the corresponding nonhuman CDR sequences.
  • Kabat numbering “Kabat definitions” and “Kabat labeling” are used interchangeably herein. These terms, which are recognized in the art, refer to a system of numbering amino acid residues which are more variable (i.e. hypervariable) than other amino acid residues in the heavy and light chain variable regions of an antibody, or an antigen binding portion thereof (Kabat et al. (1971) Ann. NY Acad, Sci. 190:382-391 and Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition , U.S. Department of Health and Human Services, NIH Publication No. 91-3242).
  • the terms “acceptor” and “acceptor antibody” refer to the antibody or nucleic acid sequence providing or encoding at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or 100% of the amino acid sequences of one or more of the framework regions.
  • the term “acceptor” refers to the antibody amino acid or nucleic acid sequence providing or encoding the constant region(s).
  • the term “acceptor” refers to the antibody amino acid or nucleic acid sequence providing or encoding one or more of the framework regions and the constant region(s).
  • the term “acceptor” refers to a human antibody amino acid or nucleic acid sequence that provides or encodes at least 80%, preferably, at least 85%, at least 90%, at least 95%, at least 98%, or 100% of the amino acid sequences of one or more of the framework regions.
  • an acceptor may contain at least 1, at least 2, at least 3, least 4, at least 5, or at least 10 amino acid residues not occurring at one or more specific positions of a human antibody.
  • acceptor framework region and/or acceptor constant region(s) may be, e.g., derived or obtained from a germline antibody gene, a mature antibody gene, a functional antibody (e.g., antibodies well-known in the art, antibodies in development, or antibodies commercially available).
  • CDR refers to the complementarity determining region within antibody variable sequences. There are three CDRs in each of the variable regions of the heavy chain and of the light chain, which are designated CDR1, CDR2 and CDR3, for each of the variable regions.
  • CDR set refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md.
  • CDR boundary definitions may not strictly follow one of the above systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding.
  • the methods used herein may utilize CDRs defined according to any of these systems, although preferred embodiments use Kabat or Chothia defined CDRs.
  • canonical residue refers to a residue in a CDR or framework that defines a particular canonical CDR structure as defined by Chothia et al. (J. Mol. Biol. 196:901-907 (1987); Chothia et al., J. Mol. Biol. 227:799 (1992), both are incorporated herein by reference). According to Chothia et al., critical portions of the CDRs of many antibodies have nearly identical peptide backbone confirmations despite great diversity at the level of amino acid sequence. Each canonical structure specifies primarily a set of peptide backbone torsion angles for a contiguous segment of amino acid residues forming a loop.
  • the terms “donor” and “donor antibody” refer to an antibody providing one or more CDRS.
  • the donor antibody is an antibody from a species different from the antibody from which the framework regions are obtained or derived.
  • the term “donor antibody” refers to a non-human antibody providing one or more CDRs.
  • the term “framework” or “framework sequence” refers to the remaining sequences of a variable region minus the CDRs. Because the exact definition of a CDR sequence can be determined using different systems, the meaning of a framework sequence is subject to correspondingly different interpretations.
  • the six CDRs (CDR-L1, -L2, and -L3 of light chain and CDR-H1, -H2, and -H3 of heavy chain) also divide the framework regions on the light chain and the heavy chain into four sub-regions (FR1, FR2, FR3 and FR4) on each chain, in which CDR1 is positioned between FR1 and FR2, CDR2 between FR2 and FR3, and CDR3 between FR3 and FR4.
  • a framework region represents the combined FR's within the variable region of a single, naturally occurring immunoglobulin chain.
  • a FR represents one of the four sub-regions, and FRs represents two or more of the four sub-regions constituting a framework region.
  • Human heavy chain and light chain acceptor sequences are known in the art.
  • germline antibody gene or “gene fragment” refers to an immunoglobulin sequence encoded by non-lymphoid cells that have not undergone the maturation process that leads to genetic rearrangement and mutation for expression of a particular immunoglobulin.
  • a particular immunoglobulin See, e.g., Shapiro et al., Crit. Rev. Immunol. 22(3): 183-200 (2002); Marchalonis et al., Adv Exp Med. Biol. 484:13-30 (2001)).
  • One of the advantages provided by various embodiments of the present invention stems from the finding that germline antibody genes are more likely than mature antibody genes are to conserve essential amino acid sequence structures characteristic of individuals in the species, hence less likely to be recognized as non-self when used in that species.
  • key residues refers to certain residues within the variable region that have more impact on the binding specificity and/or affinity of an antibody, in particular a humanized antibody.
  • a key residue includes, but is not limited to, one or more of the following: a residue that is adjacent to a CDR, a potential glycosylation site (which can be either N- or O-glycosylation site), a rare residue, a residue capable of interacting with the antigen, a residue capable of interacting with a CDR, a canonical residue, a contact residue between heavy chain variable region and light chain variable region, a residue within the Vernier zone, and a residue in the region that overlaps between the Chothia definition of a variable heavy chain CDR1 and the Kabat definition of the first heavy chain framework.
  • humanized antibody specifically refers to an antibody or a variant, derivative, analog or fragment thereof which immunospecifically binds to an antigen of interest and which comprises a framework (FR) region having substantially the amino acid sequence of a human antibody and a complementary determining region (CDR) having substantially the amino acid sequence of a non-human antibody.
  • FR framework
  • CDR complementary determining region
  • substantially in the context of a CDR refers to a CDR having an amino acid sequence at least 80%, preferably at least 85%, at least 90%, at least 95%, at least 98% or at least 99% identical to the amino acid sequence of a non-human antibody CDR.
  • a humanized antibody comprises substantially all of at least one, and typically two, variable domains (Fab, Fab′, F(ab′) 2, FabC, Fv) in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin (i.e., donor antibody) and all or substantially all of the framework regions are those of a human immunoglobulin consensus sequence.
  • a humanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin.
  • a humanized antibody contains both the light chain as well as at least the variable domain of a heavy chain.
  • the antibody also may include the CH1, hinge, CH2, CH3, and CH4 regions of the heavy chain.
  • a humanized antibody only contains a humanized light chain. In some embodiments, a humanized antibody only contains a humanized heavy chain. In specific embodiments, a humanized antibody only contains a humanized variable domain of a light chain and/or humanized heavy chain.
  • the humanized antibody can be selected from any class of immunoglobulins, including IgM, IgG, IgD, IgA and IgE, and any subclass, including without limitation IgG 1, IgG2, IgG3 and IgG4.
  • the framework and CDR regions of a humanized antibody need not correspond precisely to the parental sequences, e.g., the donor antibody CDR or the consensus framework may be mutagenized by substitution, insertion and/or deletion of at least one amino acid residue so that the CDR or framework residue at that site does not correspond exactly to either the donor antibody or the consensus framework. In a preferred embodiment, such mutations, however, will not be extensive. Usually, at least 80%, preferably at least 85%, more preferably at least 90%, and most preferably at least 95% of the humanized antibody residues will correspond to those of the parental FR and CDR sequences.
  • the term “consensus framework” refers to the framework region in the consensus immunoglobulin sequence.
  • the term “consensus immunoglobulin sequence” refers to the sequence formed from the most frequently occurring amino acids (or nucleotides) in a family of related immunoglobulin sequences (See e.g., Winnaker, From Genes to Clones, Verlagsgesellschaft, Weinheim, Germany 1987). In a family of immunoglobulins, each position in the consensus sequence is occupied by the amino acid occurring most frequently at that position in the family. Where two amino acids occur equally frequently, either can be included in the consensus sequence.
  • Vernier zone refers to a subset of framework residues that may adjust CDR structure and fine-tune the fit to antigen as described by Foote and Winter (1992, J. Mol. Biol. 224:487-499, which is incorporated herein by reference). Vernier zone residues form a layer underlying the CDRs and may impact on the structure of CDRs and the affinity of the antibody.
  • epitope includes any polypeptide determinant capable of specific binding to an immunoglobulin.
  • epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may have specific three dimensional structural characteristics, and/or specific charge characteristics.
  • An epitope is a region of an antigen that is bound by an antibody.
  • an antibody is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and/or macromolecules.
  • polynucleotide as referred to herein means a polymeric form of two or more nucleotides, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide.
  • the term includes single and double stranded forms of DNA but preferably is double-stranded DNA.
  • isolated polynucleotide shall mean a polynucleotide (e.g., of genomic, cDNA, or synthetic origin, or any combination thereof) that, by virtue of its origin, the “isolated polynucleotide” is not associated with all or a portion of a polynucleotide with which the “isolated polynucleotide” is found in nature; is operably linked to a polynucleotide that it is not linked to in nature; or does not occur in nature as part of a larger sequence.
  • vector is intended to refer to a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked.
  • plasmid refers to a circular double stranded DNA into which additional DNA segments may be ligated.
  • viral vector is another type of vector, wherein additional DNA segments may be ligated into the viral genome.
  • Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors).
  • vectors e.g., non-episomal mammalian vectors
  • vectors can be integrated into the genome of a host cell upon introduction into the host cell, and thereby are replicated along with the host genome.
  • certain vectors are capable of directing the expression of genes to which they are operatively linked.
  • Such vectors are referred to herein as “recombinant expression vectors” (or simply, “expression vectors”).
  • expression vectors of utility in recombinant DNA techniques are often in the form of plasmids.
  • plasmid and vector may be used interchangeably as the plasmid is the most commonly used form of vector.
  • the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions.
  • operably linked refers to a juxtaposition wherein the components described are in a relationship permitting them to function in their intended manner.
  • a control sequence “operably linked” to a coding sequence is connected in such a way that expression of the coding sequence is achieved under conditions compatible with the control sequences.
  • “Operably linked” sequences include both expression control sequences that are contiguous with the gene of interest and expression control sequences that act in trans or at a distance to control the gene of interest.
  • expression control sequence refers to polynucleotide sequences which are necessary to effect the expression and processing of coding sequences to which they are ligated.
  • Expression control sequences include appropriate transcription initiation, termination, promoter and enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequence); sequences that enhance protein stability; and when desired, sequences that enhance protein secretion.
  • the nature of such control sequences differs depending upon the host organism; in prokaryotes, such control sequences generally include promoter, ribosomal binding site, and transcription termination sequence; in eukaryotes, generally, such control sequences include promoters and transcription termination sequence.
  • control sequences is intended to include components whose presence is essential for expression and processing, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences.
  • Transformation refers to any process by which exogenous DNA enters a host cell. Transformation may occur under natural or artificial conditions using various methods well known in the art. Transformation may rely on any known method for the insertion of foreign nucleic acid sequences into a prokaryotic or eukaryotic host cell. The method is selected based on the host cell being transformed and may include, but is not limited to, viral infection, electroporation, lipofection, and particle bombardment. Such “transformed” cells include stably transformed cells in which the inserted DNA is capable of replication either as an autonomously replicating plasmid or as part of the host chromosome. They also include cells which transiently express the inserted DNA or RNA for limited periods of time.
  • host cell is intended to refer to a cell into which exogenous DNA has been introduced. It should be understood that such terms are intended to refer not only to the particular subject cell, but, also to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the term “host cell” as used herein.
  • host cells include prokaryotic and eukaryotic cells selected from any of the kingdoms of life. Preferred eukaryotic cells include protist, fungal, plant and animal cells.
  • host cells include but are not limited to the prokaryotic cell line E. coli ; mammalian cell lines CHO, HEK 293 and COS; the insect cell line Sf9; and the fungal cell Saccharomyces cerevisiae.
  • Standard techniques may be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection).
  • Enzymatic reactions and purification techniques may be performed according to manufacturer's specifications or as commonly accomplished in the art or as described herein.
  • the foregoing techniques and procedures may be generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification. See e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989)), which is incorporated herein by reference for any purpose.
  • Transgenic organism refers to an organism having cells that contain a transgene, wherein the transgene introduced into the organism (or an ancestor of the organism) expresses a polypeptide not naturally expressed in the organism.
  • a “transgene” is a DNA construct which is stably and operably integrated into the genome of a cell from which a transgenic organism develops, directing the expression of an encoded gene product in one or more cell types or tissues of the transgenic organism.
  • various host animals may be used for in-vivo immunization.
  • a host expressing itself an endogenous version of the antigen of interest may be used.
  • mice which had been made deficient in a particular endogenous protein via homologous recombination at the corresponding endogenous gene i.e., knockout mice
  • knockout mice have been shown to generate a humoral response to the protein with which they have been immunized and therefore to be able to be used for production of high-affinity monoclonal antibodies to the protein (see, for example, Roes, J. et al. (1995) J. Immunol. Methods 183:231-237; Lunn, M. P. et al. (2000) J. Neurochem. 75:404-412).
  • a multiplicity of nonhuman mammals are suitable hosts for antibody production in order to produce nonhuman antibodies of the invention. They include, for example, mice, rats, chickens, camelids, rabbits, sheep and goats (and knockout versions thereof), although preference is given to mice for the production of hybridoma. Furthermore, a nonhuman host animal expressing a human antibody repertoire may be used for producing essentially human antibodies to a human antigen with dual specificity. Nonhuman animals of this kind include transgenic animals (e.g., mice) bearing human immunoglobulin transgenes (chimeric hu-PBMC SCID mice) and human/mouse irradiation chimeras which are described in more detail below.
  • transgenic animals e.g., mice
  • human immunoglobulin transgenes chimeric hu-PBMC SCID mice
  • human/mouse irradiation chimeras which are described in more detail below.
  • the animal immunized is a nonhuman mammal, preferably a mouse, which is transgenic due to human immunoglobulin genes so that said nonhuman mammal makes human antibodies upon antigenic stimulation.
  • immunoglobulin transgenes for heavy and light chains with human germ line configuration are introduced into such animals which have been altered such that their endogenous heavy and light chain loci are inactive. If such animals are stimulated with antigen (e.g., with a human antigen), antibodies derived from the human immunoglobulin sequences (human antibodies) are produced. It is possible to make from the lymphocytes of such animals human monoclonal antibodies by means of standardized hybridoma technology.
  • transgenic mice with human immunoglobulins and their use in the production of human antibodies, see, for example, U.S. Pat. No. 5,939,598, WO 96/33735, WO 96/34096, WO 98/24893 and WO 99/53049 (Abgenix Inc.), and U.S. Pat. No. 5,545,806, U.S. Pat. No. 5,569,825, U.S. Pat. No. 5,625,126, U.S. Pat. No. 5,633,425, U.S. Pat. No. 5,661,016, U.S. Pat. No. 5,770,429, U.S. Pat. No. 5,814,318, U.S. Pat. No.
  • the animal which is immunized may be a mouse with severe combined immunodeficiency (SCID), which has been reconstituted with human peripheral mononuclear blood cells or lymphoid cells or precursors thereof.
  • SCID severe combined immunodeficiency
  • Such mice which are referred to as chimeric hu-PBMC SCID mice produce human immunoglobulin responses upon antigenic stimulation, as has been proved.
  • the animal which is immunized is a mouse which has been treated with a lethal does of total body irradiation, then protected from radiation with bone marrow cells from mice with severe combined immunodeficiency (SCID) and subsequently transplanted with functional human lymphocytes.
  • SCID severe combined immunodeficiency
  • This type of chimera referred to as the Trimera system, is used in order to produce human monoclonal antibodies by immunizing said mice with the antigen of interest and then producing monoclonal antibodies by using standardized hybridoma technology.
  • these mice and of their use for generating antibodies see, for example, Eren, R. et al. (1998) Immunology 93:154-161; Reisner, Y. and Dagan, S. (1998) Trends Biotechnol. 16:242-246; Ilan, E. et al. (1999) Hepatology 29:553-562; and Bocher, W. O. et al. (1999) Immunology 96:634-641.
  • monoclonal antibodies may be produced by means of standardized techniques such as the hybridoma technique originally described by Kohler and Milstein (1975 , Nature 256:495-497) (see also Brown et al. (1981) J. Immunol. 127:539-46; Brown et al. (1980) J Biol Chem 255:4980-83; Yeh et al. (1976) PNAS 76:2927-31; and Yeh et al. (1982) Int. J. Cancer 29:269-75).
  • the technology of producing monoclonal antibody hybridomas is sufficiently known (see generally R. H.
  • an immortalized cell line (typically a myeloma) is fused with lymphocytes (typically splenocytes or lymph node cells or peripheral blood lymphocytes) of a mammal immunized with the A ⁇ globulomer of the invention or derivative thereof, and the culture supernatants of the resulting hybridoma cells are screened in order to identify a hybridoma which produces a monoclonal antibody of the present invention.
  • lymphocytes typically splenocytes or lymph node cells or peripheral blood lymphocytes
  • Any of the many well known protocols for fusing lymphocytes and immortalized cell lines can be applied for this purpose (see also G. Galfre et al. (1977) Nature 266:550-52; Gefter et al. Somatic Cell Genet ., cited supra; Lerner, Yale J.
  • the immortalized cell line (e.g., a myeloma cell line) is derived from the same mammalian species as the lymphocytes.
  • murine hybridomas may be established by fusing lymphocytes from a mouse immunized with an immunogenic preparation of the invention with an immortalized mouse cell line.
  • Preferred immortalized cell lines are mouse myeloma cell lines which are sensitive to culture medium containing hypoxanthine, aminopterine and thymidine (HAT medium).
  • myeloma cell lines may be used by default as fusion partner, for example the P3-NS1/1-Ag4-1, P3-x63-Ag8.653 or Sp2/O-Ag14 myeloma lines.
  • These myeloma cell lines are available from the American Type Culture Collection (ATCC), Manassas, Va.
  • ATCC American Type Culture Collection
  • PEG polyethylene glycol
  • Hybridoma cells resulting from the fusion are then selected using HAT medium, thereby killing unfused and unproductively fused myeloma cells (unfused splenocytes die after several days because they are not transformed).
  • Hybridoma cells producing monoclonal antibodies of the invention are identified by screening the hybridoma culture supernatants for such antibodies, for example, by using a dot blot assay in order to select those antibodies which have the binding affinities as defined above.
  • the monoclonal antibodies 10F4 and 3C5 all have been generated using the above-described in-vivo approach and thereof are obtainable from a hybridoma as defined herein.
  • said hybridoma can be used as a source of nucleic acid encoding light and/or heavy chains in order to recombinantly produce antibodies of the present invention, as is described below in further detail.
  • antibodies of the invention may be identified and isolated by screening recombinant combinatorial immunoglobulin libraries to thereby isolate immunoglobulin library members which have the required binding affinity.
  • Kits for generating and screening display libraries are commercially available (e.g. the Pharmacia Recombinant Phage Antibody System, catalog No. 27-9400-01; and the Stratagene SurfZAP® Phage Display Kit, catalog No. 240612).
  • the display library is an scFv library or an Fab library. The phage display technique for screening recombinant antibody libraries has been adequately described.
  • WO 97/29131 (describes production of a recombinant human antibody to a human antigen (human tumor necrosis factor alpha) and also in-vitro affinity maturation of the recombinant antibody) and Salfeld et al., U.S. Provisional Patent Application No. 60/126,603 and the patent applications based hereupon (likewise describes production of recombinant human antibodies to human antigen (human interleukin-12), and also in-vitro affinity maturation of the recombinant antibody).
  • recombinant antibody libraries may be expressed on the surface of yeast cells or of bacterial cells.
  • WO 99/36569 describes methods of preparing and screening libraries expressed on the surface of yeast cells.
  • WO 98/49286 describes in more detail methods of preparing and screening libraries expressed on the surface of bacterial cells.
  • a selection process for enriching recombinant antibodies with the desired properties form an integral part of the process, which is generally referred to as “panning” and often takes the form of affinity chromatography over columns to whose matrix the target structure has been attached.
  • Promising candidate molecules are then subjected to individual determination of their absolute and/or relative affinities, preferably by means of a standardized dot blot assay.
  • the DNA sequences encoding the light and heavy chains of said antibody are isolated by means of standardized molecular-biological techniques, for example, by means of PCR amplification of DNA from the display package (e.g., the phage) which has been isolated during library screening.
  • Nucleotide sequences of genes for light and heavy antibody chains, which may be used for preparing PCR primers, are known to one of ordinary skill in the art. A multiplicity of such sequences are described, for example, in Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition , U.S. Department of Health and Human Services, NIH Publication No. 91-3242 and in the database of sequences of the human germ line VBASE.
  • An antibody or antibody moiety of the invention may be produced by recombinantly expressing the genes for light and heavy immunoglobulin chains in a host cell.
  • a host cell is transfected with one or more recombinant expression vectors carrying DNA fragments encoding the light and heavy immunoglobulin chains of said antibody, thereby expressing the light and heavy chains in the host cell and secreting them preferably into the medium in which said host cells are cultured.
  • the antibodies can be isolated from this medium. Standardized recombinant DNA methods are used in order to obtain genes for heavy and light antibody chains, to insert said genes into recombinant expression vectors and to introduce said vectors into host cells.
  • DNA fragments encoding VH and VL segments of the antibody of interest may be further manipulated using standardized recombinant DNA techniques, for example, in order to convert the genes for variable regions to genes for full length antibody chains, to genes for Fab fragments or to an scFv gene.
  • These manipulations comprise linking a VL- or VH-encoding DNA fragment operatively to another DNA fragment encoding another protein, for example a constant antibody region or a flexible linker.
  • the term “operatively linked” is to be understood here as meaning that the two DNA fragments are linked in such a way that the amino acid sequences encoded by said two DNA fragments remain in frame.
  • the isolated DNA encoding the VH region may be converted to a gene for a full length heavy chain by operatively linking the VH-region encoding DNA with another DNA molecule encoding heavy chain constant regions (CH1, CH2 and CH3).
  • CH1, CH2 and CH3 DNA molecule encoding heavy chain constant regions
  • the sequences of human heavy chain constant region genes are well known (see, for example, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition , U.S. Department of Health and Human Services, NIH Publication No. 91-3242), and DNA fragments spanning said regions may be obtained by means of standardized PCR amplification.
  • the heavy chain constant region may be a constant region from IgG1, IgG2, IgG3, IgG4, IgM, IgA, IgE or IgD, with preference being given to a constant region from IgG, in particular IgG1 or IgG4.
  • the VH-encoding DNA may be operatively linked to another DNA molecule encoding merely the heavy chain constant region CH1.
  • the isolated DNA encoding the VL region may be converted to a gene for a full length light chain (and a gene for an Fab light chain) by operatively linking the VL-encoding DNA to another DNA molecule encoding the light chain constant region CL.
  • the sequences of genes of the constant region of human light chain are well known (see Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition , U.S. Department of Health and Human Services, NIH Publication No. 91-3242), and DNA fragments spanning said regions may be obtained by means of standardized PCR amplification.
  • the light chain constant region may be a constant kappa or lambda region, a constant kappa region being preferred.
  • the VH- and VL-encoding DNA fragments may be operatively linked to another fragment encoding a flexible linker, for example the amino acid sequence (Gly 4 -Ser) 3 so that the VH and VL sequences are expressed as a continuous single-chain protein, with the VL and VH regions being linked to one another via said flexible linker (see Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., Nature (1990) 348:552-554).
  • a flexible linker for example the amino acid sequence (Gly 4 -Ser) 3 so that the VH and VL sequences are expressed as a continuous single-chain protein, with the VL and VH regions being linked to one another via said flexible linker
  • Single domain VH and VL having the binding affinities as described above may be isolated from single domain libraries by the above-described methods.
  • Two VH single-domain chains (with or without CH1) or two VL chains or a pair of one VH chain and one VL chain with the desired binding affinity may be useful as described herein for the antibodies of the invention.
  • the DNAs encoding partial or full length light and heavy chains may be inserted into expression vectors so as to operatively link the genes to appropriate transcriptional and translational control sequences.
  • operatively linked is to be understood to mean that an antibody gene is ligated in a vector in such a way that transcriptional and translational control sequences within the vector fulfill their intended function of regulating transcription and translation of said antibody gene.
  • the expression vector and the expression control sequences are chosen so as to be compatible with the expression host cell used.
  • the gene for the antibody light chain and the gene for the antibody heavy chain may be inserted into separate vectors or both genes are inserted into the same expression vector, this being the usual case.
  • the antibody genes are inserted into the expression vector by means of standardized methods (for example by ligation of complementary restriction cleavage sites on the antibody gene fragment and the vector, or by ligation of blunt ends, if no restriction cleavage sites are present).
  • the expression vector may already carry sequences for antibody constant regions prior to insertion of the sequences for the light and heavy chains.
  • one approach is to convert the VH and VL sequences to full length antibody genes by inserting them into expression vectors already encoding the heavy and, respectively, light chain constant regions, thereby operatively linking the VH segment to the CH segment(s) within the vector and also operatively linking the VL segment to the CL segment within the vector.
  • the recombinant expression vector may encode a signal peptide which facilitates secretion of the antibody chain from the host cell.
  • the gene for said antibody chain may be cloned into the vector, thereby linking the signal peptide in frame to the N terminus of the gene for the antibody chain.
  • the signal peptide may be an immunoglobulin signal peptide or a heterologous signal peptide (i.e. a signal peptide from a non-immunoglobulin protein).
  • the expression vectors of the invention may have regulatory sequences controlling expression of the genes for the antibody chain in a host cell.
  • regulatory sequence is intended to include promoters, enhancers and further expression control elements (e.g. polyadenylation signals) which control transcription or translation of the genes for the antibody chain. Regulatory sequences of this kind are described, for example, in Goeddel; Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990). The skilled worker will appreciate that the expression vector design which includes selection of regulatory sequences may depend on factors such as the choice of the host cell to be transformed, the desired strength of expression of the protein, etc.
  • Preferred regulatory sequences for expression in mammalian host cells include viral elements resulting in strong and constitutive protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV) (such as the CMV promoter/enhancer), simian virus 40 (SV40) (such as the SV40 promoter/enhancer), adenovirus (e.g., the adenovirus major late promoter (AdMLP)) and polyoma.
  • CMV cytomegalovirus
  • SV40 simian virus 40
  • AdMLP adenovirus
  • AdMLP adenovirus major late promoter
  • the recombinant expression vectors of the invention may have additional sequences such as those which regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes.
  • the selectable marker genes facilitate the selection of host cells into which the vector has been introduced (see, for example, U.S. Pat. Nos. 4,399,216, 4,634,665 and 5,179,017, all to Axel et al.).
  • Preferred selectable marker genes include the gene for dihydrofolate reductase (DHFR) (for use in dhfr ⁇ host cells with methotrexate selection/amplification) and the neo gene (for G418 selection).
  • DHFR dihydrofolate reductase
  • neo gene for G418 selection.
  • the expression vector(s) encoding said heavy and light chains is(are) transfected into a host cell by means of standardized techniques.
  • the various forms of the term “transfection” are intended to comprise a multiplicity of techniques customarily used for introducing exogenous DNA into a prokaryotic or eukaryotic host cell, for example electroporation, calcium phosphate precipitation, DEAE-dextran transfection, and the like.
  • the antibodies of the invention are expressed either in prokaryotic or eukaryotic host cells
  • Prokaryotic expression of antibody genes has been reported as being ineffective for production of high yields of active antibody (Boss, M. A. and Wood, C. R. (1985) Immunology Today 6:12-13).
  • Preferred mammalian host cells for expressing recombinant antibodies of the invention include CHO cells (including dhfr ⁇ CHO cells described in Urlaub and Chasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, which are used together with a DHFR-selectable marker, as described, for example, in R. J. Kaufman and P. A. Sharp (1982) Mol. Biol. 159:601-621), NS0 myeloma cells, COS cells and SP2 cells.
  • the antibodies When introducing recombinant expression vectors encoding the antibody genes into mammalian host cells, the antibodies are produced by culturing the host cells until the antibody is expressed in said host cells or, preferably, the antibody is secreted into the culture medium in which the host cells grow. The antibodies may then be isolated from the culture medium by using standardized protein purification methods. It is likewise possible to use host cells in order to produce moieties of intact antibodies, such as Fab fragments or scFv molecules. Variations of the above-described procedure are of course included in the invention. For example, it may be desirable to transfect a host cell with DNA encoding either the light chain or the heavy chain (but not both) of an antibody of the invention.
  • the DNA encoding either such a light or such a heavy chain or both may be removed partially or completely by means of recombinant DNA technology. Molecules expressed by such truncated DNA molecules are likewise included in the antibodies of the invention.
  • a recombinant expression vector encoding both the antibody heavy chain and the antibody light chain is introduced into dhfr ⁇ CHO cells by means of calcium phosphate-mediated transfection.
  • the genes for the heavy and light antibody chains are in each case operatively linked to regulatory CMV enhancer/AdMLP-promoter elements in order to effect strong transcription of said genes.
  • the recombinant expression vector also carries a DHFR gene which can be used for selecting dhfr ⁇ CHO cells transfected with the vector by using methotrexate selection/amplification.
  • the selected transformed host cells are cultured so that the heavy and light antibody chains are expressed, and intact antibody is isolated from the culture medium.
  • Standardized molecular-biological techniques are used in order to prepare the recombinant expression vector, to transfect the host cells, to select the transformants, to culture said host cells, and to obtain the antibody from the culture medium.
  • the invention relates to a method of synthesizing a recombinant antibody of the invention by culturing a host cell of the invention in a suitable culture medium until a recombinant antibody of the invention has been synthesized.
  • the method may further comprise isolating said recombinant antibody from said culture medium.
  • RNA-protein fusions As an alternative to screening recombinant antibody libraries by phage display, other methods known to the skilled worker may be used for screening large combinatorial libraries to identify the antibodies of the invention. Basically, any expression system in which a close physical linkage between a nucleic acid and the antibody encoded thereby is established and may be used to select a suitable nucleic acid sequence by virtue of the properties of the antibody it encodes may be employed.
  • the recombinant antibody library is expressed in the form of RNA-protein fusions, as described in WO 98/31700 to Szostak and Roberts, and in Roberts, R. W. and Szostak, J. W. (1997) Proc. Natl. Acad. Sci.
  • a specific mRNA of a complex mixture of mRNAs may be concentrated on the basis of the properties of the encoded peptide or protein (e.g. of the antibody or a moiety thereof), such as binding of said antibody or said moiety thereof to A ⁇ (12-42) globulomer or a derivative thereof.
  • Nucleic acid sequences which encode antibodies or moieties thereof and which are obtained by screening of such libraries may be expressed by recombinant means in the above-described manner (e.g. in mammalian host cells) and may, in addition, be subjected to further affinity maturation by either screening in further rounds mRNA-peptide fusions, introducing mutations into the originally selected sequences), or using other methods of in-vitro affinity maturation of recombinant antibodies in the above-described manner.
  • the antibodies of the invention may likewise be produced by using a combination of in-vivo and in-vitro approaches such as methods in which A ⁇ (12-42) globulomer or a derivative thereof is first allowed to act on an antibody repertoire in a host animal in vivo to stimulate production of A ⁇ (12-42) globulomer or derivative-binding antibodies and then further antibody selection and/or antibody maturation (i.e., optimization) are accomplished with the aid of one or more in-vitro techniques.
  • in-vivo and in-vitro approaches such as methods in which A ⁇ (12-42) globulomer or a derivative thereof is first allowed to act on an antibody repertoire in a host animal in vivo to stimulate production of A ⁇ (12-42) globulomer or derivative-binding antibodies and then further antibody selection and/or antibody maturation (i.e., optimization) are accomplished with the aid of one or more in-vitro techniques.
  • a combined method of this kind may comprise firstly immunizing a nonhuman animal (e.g., a mouse, rat, rabbit, chicken, camelid, sheep or goat or a transgenic version thereof or a chimeric mouse) with said A ⁇ (12-42) globulomer or derivative thereof to stimulate an antibody response to the antigen and then preparing and screening a phage display antibody library by using immunoglobulin sequences of lymphocytes which have been stimulated in vivo by the action of said A ⁇ (12-42) globulomer or derivative.
  • the first step of this combined procedure may be carried out in the manner described above in connection with the in-vivo approaches, while the second step of this procedure may be carried out in the manner described above in connection with the in-vitro approaches.
  • Preferred methods of hyperimmunizing nonhuman animals with subsequent in-vitro screening of phage display libraries prepared from said stimulated lymphocytes include those described by BioSite Inc., see, for example, WO 98/47343, WO 91/17271, U.S. Pat. No. 5,427,908 and U.S. Pat. No. 5,580,717.
  • a combined method comprises firstly immunizing a nonhuman animal (e.g., a mouse, rat, rabbit, chicken, camelid, sheep, goat or a knockout and/or transgenic version thereof, or a chimeric mouse) with an A ⁇ (12-42) globulomer of the invention or derivative thereof to stimulate an antibody response to said A ⁇ (12-42) globulomer or derivative thereof and selecting the lymphocytes which produce the antibodies having the desired specificity by screening hybridomas (prepared, for example, from the immunized animals).
  • a nonhuman animal e.g., a mouse, rat, rabbit, chicken, camelid, sheep, goat or a knockout and/or transgenic version thereof, or a chimeric mouse
  • the genes for the antibodies or single domain antibodies are isolated from the selected clones (by means of standardized cloning methods such as reverse transcriptase polymerase chain reaction) and subjected to in-vitro affinity maturation in order to improve thereby the binding properties of the selected antibody or the selected antibodies.
  • the first step of this procedure may be conducted in the manner described above in connection with the in-vivo approaches, while the second step of this procedure may be conducted in the manner described above in connection with the in-vitro approaches, in particular by using methods of in-vitro affinity maturation, such as those described in WO 97/29131 and WO 00/56772.
  • the recombinant antibodies are generated from individual isolated lymphocytes by using a procedure which is known to the skilled worker as selected lymphocyte antibody methods (SLAM) and which is described in U.S. Pat. No. 5,627,052, WO 92/02551 and Babcock, J. S. et al. (1996) Proc. Natl. Acad. Sci. USA 93:7843-7848.
  • SAM selected lymphocyte antibody methods
  • a nonhuman animal e.g., a mouse, rat, rabbit, chicken, camelid, sheep, goat, or a transgenic version thereof, or a chimeric mouse
  • a ⁇ (12-42) globulomer or a derivative thereof to stimulate an immune response to said oligomer or derivative
  • individual cells secreting antibodies of interest are selected by using an antigen-specific haemolytic plaque assay.
  • the globulomer or derivative thereof or structurally related molecules of interest may be coupled to sheep erythrocytes, using a linker such as biotin, thereby making it possible to identify individual cells secreting antibodies with suitable specificity by using the haemolytic plaque assay.
  • variable regions of the light and heavy chains are obtained from the cells by reverse transcriptase PCR, and said variable regions may then be expressed in association with suitable immunoglobulin constant regions (e.g., human constant regions) in mammalian host cells such as COS or CHO cells.
  • suitable immunoglobulin constant regions e.g., human constant regions
  • the host cells transfected with the amplified immunoglobulin sequences derived from in vivo-selected lymphocytes may then be subjected to further in-vitro analysis and in-vitro selection by spreading out the transfected cells, for example, in order to isolate cells expressing antibodies with the binding affinity.
  • the amplified immunoglobulin sequences may furthermore be manipulated in vitro.
  • Antibodies having the required affinities defined herein can be selected by performing a dot blot essentially as described above. Briefly, the antigen is attached to a solid matrix, preferably dotted onto a nitrocellulose membrane, in serial dilutions. The immobilized antigen is then contacted with the antibody of interest followed by detection of the latter by means of an enzyme-conjugated secondary antibody and a colorimetric reaction; at defined antibody and antigen concentrations, the amount of antibody bound allows affinity determination.
  • the relative affinity of two different antibodies to one target, or of one antibody to two different targets is here defined as the relation of the respective amounts of target-bound antibody observed with the two antibody-target combinations under otherwise identical dot blot conditions.
  • Antibodies which bind to the same epitope as monoclonal antibody 10F4 or 3C5 can be obtained in a manner known per se.
  • target structures are herein said to be “competing” for a particular antibody if at least one of these structures is capable of specifically reducing the measurable binding of another, preferably by offering an overlapping or identical epitope, more preferably an identical epitope.
  • Competing target entities are useful for directly selecting antibodies by virtue of their relative affinity to such target structures. Relative affinities may thus be determined directly by using a competition assay in which distinguishable forms of the competing entities, e.g., differently labelled competing structures, are contacted with the antibody of interest, and the relative affinity of the antibody to each of these entities is deduced from the relative amounts of these entities which are bound by the antibody.
  • Such competition may be used to directly enrich for antibodies possessing a desired relative affinity to the target entity, by attaching the entity towards which greater affinity is desired to a solid matrix support and adding a suitable amount, preferably a molar excess, of the competing entity towards which smaller affinity is desired to the medium.
  • the antibodies displaying the desired relative affinities will tend to bind to the matrix more strongly than others and may be obtained after washing out the less desirable forms, e.g., by washing out at low salt concentrations and then harvesting the bound antibody by reversibly detaching it from its target by using high salt concentrations.
  • several rounds of enrichment may be performed.
  • the genotype underlying an antibody is physically linked to this antibody, e.g., in a pool of hybridomas or antigen-displaying phages or yeast cells, the corresponding phenotype may be rescued.
  • a modified dot blot is used where the immobilized antigen competes with a solved entity for antibody binding, so that the relative affinity of the antibody can be deduced from the percentage bound to the immobilized antigen.
  • Antibody moieties such as Fab and F(ab′) 2 fragments may be produced from whole antibodies by using conventional techniques such as digestion with papain or pepsin.
  • antibodies, antibody moieties and immunoadhesion molecules may be obtained by using standardized recombinant DNA techniques.
  • compositions comprising an antibody of the invention and, optionally, a pharmaceutically suitable carrier.
  • Pharmaceutical compositions of the invention may furthermore contain at least one additional therapeutic agent, for example one or more additional therapeutic agents for the treatment of a disease for whose relief the antibodies of the invention are useful. If, for example, the antibody of the invention binds to a globulomer of the invention, the pharmaceutical composition may furthermore contain one or more additional therapeutic agents useful for the treatment of disorders in which the activity of said globulomer is important.
  • Pharmaceutically suitable carriers include any solvents, dispersing media, coatings, antibacterial and antifungal agents, isotonic and absorption-delaying agents, and the like, as long as they are physiologically compatible.
  • Pharmaceutically acceptable carriers include, for example, water, saline, phosphate-buffered saline, dextrose, glycerol, ethanol and the like, and combinations thereof. In many cases, preference is given to using isotonic agents, for example sugars, polyalcohols such as mannitol or sorbitol, or sodium chloride in addition. Pharmaceutically suitable carriers may furthermore contain relatively small amounts of auxiliary substances such as wetting agents or emulsifiers, preservatives or buffers, which increase the half life or efficacy of the antibodies.
  • the pharmaceutical compositions may be suitable for parenteral administration, for example.
  • the antibodies are prepared preferably as injectable solutions with an antibody content of 0.1-250 mg/mL.
  • the injectable solutions may be prepared in liquid or lyophilized form, the dosage form being a flint glass or vial, an ampoule or a filled syringe.
  • the buffer may contain L-histidine (1-50 mM, preferably 5-10 mM) and have a pH of 5.0-7.0, preferably of 6.0.
  • Further suitable buffers include, without being limited thereto, sodium succinate, sodium citrate, sodium phosphate or potassium phosphate buffers.
  • Sodium chloride may be used in order to adjust the tonicity of the solution to a concentration of 0-300 mM (preferably 150 mM for a liquid dosage form).
  • Cryoprotectants for example sucrose (e.g., 0-10%, preferably 0.5-1.0%) may also be included for a lyophilized dosage form.
  • Other suitable cryoprotectants are trehalose and lactose.
  • Fillers for example mannitol (e.g., 1-10%, preferably 2-4%) may also be included for a lyophilized dosage form.
  • Stabilizers for example L-methionine (e.g., 51-50 mM, preferably 5-10 mM) may be used both in liquid and lyophilized dosage forms.
  • Further suitable fillers are glycine and arginine.
  • Surfactants for example, polysorbate 80 (e.g., 0-0.05%, preferably 0.005-0.01%), may also be used.
  • Further surfactants are polysorbate 20 and BRIJ surfactants.
  • compositions of the invention may have a multiplicity of forms. These include liquid, semisolid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the preferred form depends on the intended type of administration and on the therapeutic application. Typically, preference is given to compositions in the form of injectable or infusible solutions, for example compositions which are similar to other antibodies for passive immunization of humans.
  • the preferred route of administration is parenteral (e.g., intravenous, subcutaneous, intraperitoneal or intramuscular). According to a preferred embodiment, the antibody is administered by intravenous infusion or injection.
  • the antibody is administered by intramuscular or subcutaneous injection.
  • Therapeutic compositions must typically be sterile and stable under preparation and storage conditions.
  • the compositions may be formulated as solutions, microemulsions, dispersions, liposomes or other ordered structures suitable for high concentrations of active substance.
  • Sterile injectable solutions may be prepared by introducing the active compound (i.e., the antibody) in the required amount into a suitable solvent, where appropriate with one or a combination of the abovementioned ingredients, as required, and then sterile-filtering said solution.
  • Dispersions are usually prepared by introducing the active compound into a sterile vehicle containing a basic dispersion medium and, where appropriate, other required ingredients.
  • a sterile lyophilized powder for preparing sterile injectable solutions vacuum drying and spray drying are preferred methods of preparation, which produces a powder of the active ingredient and, where appropriate, of further desired ingredients from a previously sterile-filtered solution.
  • the correct flowability of a solution may be maintained by using, for example, a coating such as lecithin, by maintaining, in the case of dispersions the required particle size or by using surfactants.
  • a prolonged absorption of injectable compositions may be achieved by additionally introducing into the composition an agent which delays absorption, for example monostearate salts and gelatine.
  • the antibodies of the invention may be administered by a multiplicity of methods known to the skilled worker, although the preferred type of administration for many therapeutic applications is subcutaneous injection, intravenous injection or infusion.
  • the active compound may be prepared with a carrier which protects the compound against rapid release, such as, for example, a formulation with sustained or controlled release, which includes implants, transdermal plasters and microencapsulated release systems.
  • a carrier which protects the compound against rapid release
  • a carrier which protects the compound against rapid release
  • a formulation with sustained or controlled release which includes implants, transdermal plasters and microencapsulated release systems.
  • Biologically degradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid may be used.
  • the methods of preparing such formulations are well known to the skilled worker; see, for example, Sustained and Controlled Release Drug Delivery Systems , J. R. Robinson, ed., Marcel Dekker, Inc., New
  • an antibody of the invention may be administered orally, for example, in an inert diluent or a metabolizable edible carrier.
  • the antibody (and further ingredients, if desired) may also be enclosed in a hard or soft gelatine capsule, compressed to tablets or added directly to food.
  • the antibodies may be mixed with excipients and used in the form of oral tablets, buccal tablets, capsules, elixirs, suspensions, syrups and the like. If it is intended to administer an antibody of the invention via a route other than the parenteral one, it may be necessary to choose a coating from a material which prevents its inactivation.
  • the present invention also relates to a method of inhibiting the activity of globulomers of the invention in an individual which suffers from a disorder in which the amyloid ⁇ protein is involved and in which in particular the activity of said globulomers of the invention is important.
  • Said method comprises the administration of at least one antibody of the invention to the individual with the aim of inhibiting the activity of the globulomer to which the antibody binds.
  • Said individual is preferably a human being.
  • An antibody of the invention may be administered for therapeutic purposes to a human individual.
  • an antibody of the invention may be administered to a nonhuman mammal for veterinary purposes or within the framework of an animal model for a particular disorder. Such animal models may be useful for evaluating the therapeutic efficacy of antibodies of the invention (for example for testing dosages and time courses of administration).
  • disorders in which the globulomers of the invention play a part include, in particular, disorders in whose development and/or progression a globulomer of the invention is involved. These are in particular those disorders in which globulomers of the invention are evidently or presumably responsible for the pathophysiology of said disorder or are a factor which contributes to the development and/or progression of said disorder. Accordingly, those disorders are included here in which inhibition of the activity of globulomers of the invention can relieve symptoms and/or progression of the disorder. Such disorders can be verified, for example, by an increased concentration of globulomers of the invention in a biological fluid of an individual suffering from a particular disorder (e.g., increased concentration in serum, plasma, CSF, urine, etc.). This may be detected, for example, by using an antibody of the invention.
  • the globulomers of the invention play an important part in the pathology associated with a multiplicity of disorders in which neurodegenerative elements, cognitive deficiencies, neurotoxic elements and inflammatory elements are involved.
  • disorders that can be treated or prevented include those associated with amyloidoses.
  • amyloidoses herein denotes a number of disorders characterized by abnormal folding, clumping, aggregation and/or accumulation of particular proteins (amyloids, fibrous proteins and their precursors) in various tissues of the body.
  • nerve tissue is affected, and in cerebral amyloid angiopathy (CAA) blood vessels are affected.
  • CAA cerebral amyloid angiopathy
  • compositions of the invention may include a “therapeutically effective amount” or a “prophylactically effective amount” of an antibody or antibody moiety of the invention.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
  • a therapeutically effective amount of the antibody or antibody moiety may be determined by a person skilled in the art and may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the antibody or antibody moiety to elicit a desired response in the individual.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of the antibody or antibody portion are outweighed by the therapeutically beneficial effects.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.
  • the present invention includes a further method of preventing or treating Alzheimer's disease in a patient in need of such prevention or treatment.
  • This method comprises the step of administering the vaccine noted above to the patient in an amount sufficient to effect the prevention or treatment.
  • the present invention encompasses a method of identifying compounds suitable for active immunization of a patient predicted to develop an amyloidosis, e.g. Alzheimer's disease.
  • This method comprises: 1) exposing one or more compounds of interest to one or more of the antibodies described above for a time and under conditions sufficient for the one or more compounds to bind to the antibody or antibodies; 2) identifying those compounds which bind to the antibody or antibodies, the identified compounds to be used in active immunization in a patient predicated to develop an amyloidosis, e.g., Alzheimer's disease.
  • the antibodies of the invention advantageously have detection threshold concentrations of less than 10 ng/mL of sample, preferably of less than 1 ng/mL of sample and particularly preferably of less than 100 ⁇ g/mL of sample, meaning that at least the concentration of globulomer per mL of sample, indicated in each case, advantageously also lower concentrations, can be detected by the antibodies of the invention.
  • the detection is carried out immunologically.
  • This may be carried out, in principle, by using any analytical or diagnostic assay method in which antibodies are used, including agglutination and precipitation techniques, immunoassays, immunohistochemical methods and immunoblot techniques, for example Western blotting or, preferably, dot blot methods.
  • analytical or diagnostic assay method including agglutination and precipitation techniques, immunoassays, immunohistochemical methods and immunoblot techniques, for example Western blotting or, preferably, dot blot methods.
  • In vivo methods for example imaging methods, are also included here.
  • immunoassays are advantageous.
  • Competitive immunoassays i.e., assays where antigen and labelled antigen (tracer) compete for antibody binding
  • sandwich immunoassays i.e., assays where binding of specific antibodies to the antigen is detected by a second, usually labelled antibody
  • assays may be either homogeneous, i.e., without separation into solid and liquid phases, or heterogeneous, i.e., bound labels are separated from unbound ones, for example, via solid phase-bound antibodies.
  • the various heterogeneous and homogeneous immunoassay formats can be classified into particular classes, for example RIAs (radioimmunoassays), ELISA (enzyme-linked immunosorbent assay), FIA (fluorescence immunoassay), LIA (luminescence immunoassay), TRFIA (time-resolved FIA), IMAC (immunoactivation), EMIT (enzyme-multiplied immune test), TIA (turbidometric immunoassay), I-PCR (immuno-PCR).
  • RIAs radioimmunoassays
  • ELISA enzyme-linked immunosorbent assay
  • FIA fluorescence immunoassay
  • LIA luminescence immunoassay
  • TRFIA time-resolved FIA
  • IMAC immunoactivation
  • EMIT enzyme-multiplied immune test
  • TIA turbidometric immunoassay
  • I-PCR immuno-PCR
  • globulomer quantification of the invention preference is given to competitive immunoassays in which a defined amount of labelled globulomer derivative serving as tracer competes with the globulomer of the sample (containing an unknown amount of unlabelled globulomers) to be quantified for binding to the antibody used.
  • the amount of antigen, i.e., the amount of globulomer, in the sample can be determined from the amount of the displaced tracer with the aid of a standard curve.
  • enzymes have proved advantageous.
  • Systems based on peroxidases in particular, horseradish peroxidase, alkaline phosphatase and ⁇ -D-galactosidase, may be used, for example.
  • Specific substrates whose conversion can be monitored photometrically, for example, are available for these enzymes.
  • Suitable substrate systems are based on p-nitrophenyl phosphate (p-NPP), 5-bromo-4-chloro-3-indolyl phosphate/nitroblue tetrazolium (BCIP/NPT), Fast-Red/naphthol-AS-TS phosphate for alkaline phosphatase; 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), o-phenylenediamine (OPT), 3,3′,5,5′-tetramethylbenzidine (TMB), o-dianisidine, 5-aminosalicylic acid, 3-dimethylaminobenzoic acid (DMAB) and 3-methyl-2-benzothiazolinehydrazone (MBTH) for peroxidases; o-nitrophenyl- ⁇ -D-galactoside (o-NPG), p-nitrophenyl- ⁇ -D-galactoside and 4-methylumbelliphenyl- ⁇ -D-gal
  • these substrate systems are commercially available in a ready-to-use form, for example in the form of tablets which may also contain further reagents such as appropriate buffers and the like.
  • the tracers used may be labelled globulomers. In this sense, a particular globulomer can be determined by labelling the globulomer to be determined and using it as tracer. The coupling of labels to globulomers for preparing tracers may be carried out in a manner known per se. The comments above on derivatization of globulomers of the invention are referred to by analogy.
  • a number of labels appropriately modified for conjugation to proteins are available, for example biotin-, avidin-, extravidin- or streptavidin-conjugated enzymes, maleimide-activated enzymes and the like. These labels may be reacted directly with the oligomer or, if required, with the appropriately derivatized globulomer to give the tracer. If, for example, a streptavidin-peroxidase conjugate is used, then this firstly requires biotinylation of the globulomer. This applies correspondingly to the reverse order. Suitable methods to this end are also known to the skilled worker.
  • the antigen-antibody complex may be separated by binding it to the support, for example via an anti-idiotypical antibody coupled to said support, e.g. an antibody directed against rabbit IgG.
  • an anti-idiotypical antibody coupled to said support, e.g. an antibody directed against rabbit IgG.
  • Appropriate supports, in particular microtiter plates coated with appropriate antibodies, are known and partly commercially available.
  • the present invention further relates to immunoassay sets having at least one antibody as described above and further components.
  • Said sets are, usually in the form of a packaging unit, a combination of means for carrying out a globulomer determination of the invention.
  • said means are preferably provided in an essentially ready-to-use form.
  • An advantageous arrangement offers the immunoassay in the form of a kit.
  • a kit usually comprises multiple containers for separate arrangement of components. All components may be provided in a ready-to-use dilution, as a concentrate for diluting or as a dry substance or lyophilisate for dissolving or suspending; individual or all components may be frozen or stored at room temperature until use.
  • Sera are preferably shock-frozen, for example at ⁇ 20° C. so that in these cases an immunoassay has to be kept preferably at temperatures below freezing prior to use. Further components supplied with the immunoassay depend on the type of said immunoassay. Usually, standard protein, tracer which may or may not be required and control serum are supplied together with the antiserum. Furthermore, microtiter plates, preferably antibody-coated, buffers, for example, for testing, for washing or for conversion of the substrate, and the enzyme substrate itself may also be included.
  • the present invention also includes a method of diagnosing an amyloidosis, e.g., Alzheimer's disease, in a patient suspected of having this disease.
  • This method comprises the steps of: 1) isolating a biological sample from the patient; 2) contacting the biological sample with at least one of the antibodies described above for a time and under conditions sufficient for formation of antigen/antibody complexes; and 3) detecting presence of the antigen/antibody complexes in said sample, presence of the complexes indicating a diagnosis of an amyloidosis, e.g., Alzheimer's disease, in the patient.
  • the antigen may be, for example, an globulomer or a portion or fragment thereof which has the same functional properties as the full globulomer (e.g., binding activity).
  • the present invention includes another method of diagnosing an amyloidosis, e.g., Alzheimer's disease in a patient suspected of having this disease.
  • This method comprising the steps of: 1) isolating a biological sample from the patient; 2) contacting the biological sample with an antigen for a time and under conditions sufficient for the formation of antibody/antigen complexes; 3) adding a conjugate to the resulting antibody/antigen complexes for a time and under conditions sufficient to allow the conjugate to bind to the bound antibody, wherein the conjugate comprises one of the antibodies described above, attached to a signal generating compound capable of generating a detectable signal; and 4) detecting the presence of an antibody which may be present in the biological sample, by detecting a signal generated by the signal generating compound, the signal indicating a diagnosis of an amyloidosis, e.g., Alzheimer's disease in the patient.
  • the antigen may be a globulomer or a portion or fragment thereof having the same functional properties as the full glob
  • the present invention includes an additional method of diagnosing an amyloidosis, e.g., Alzheimer's disease, in a patient suspected of having an amyloidosis, e.g., Alzheimer's disease.
  • This method comprises the steps of: 1) isolating a biological sample from said patient; 2) contacting the biological sample with anti-antibody, wherein the anti-antibody is specific for one of the antibodies described above, for a time and under conditions sufficient to allow for formation of anti-antibody/antibody complexes, the complexes containing antibody present in the biological sample; 2) adding a conjugate to resulting anti-antibody/antibody complexes for a time and under conditions sufficient to allow the conjugate to bind to bound antibody, wherein the conjugate comprises an antigen, which binds to a signal generating compound capable of generating a detectable signal; and 3) detecting a signal generated by the signal generating compound, the signal indicating a diagnosis of an amyloidosis, e.g., Alzheimer's
  • the present invention includes a kit comprising: a) at least one of the antibodies described above and b) a conjugate comprising an antibody attached to a signal-generating compound, wherein the antibody of the conjugate is different from the isolated antibody.
  • the present invention also encompasses a kit comprising: a) an anti-antibody to one of the antibodies described above and b) a conjugate comprising an antigen attached to a signal-generating compound.
  • the antigen may be a globulomer or a fragment or portion thereof having the same functional characteristics as the globulomer (e.g., binding activity).
  • an antibody of the present invention is coated on a solid phase (or is present in a liquid phase).
  • the test or biological sample e.g., whole blood, cerebrospinal fluid, serum, etc.
  • antigen e.g., globulomer
  • the direct method comprises simply detecting presence of the complex itself and thus presence of the antigens.
  • a conjugate is added to the bound antigen.
  • the conjugate comprises a second antibody, which binds to the bound antigen, attached to a signal-generating compound or label.
  • the signal-generating compound If the second antibody bind to the bound antigen, the signal-generating compound generates a measurable signal. Such signal then indicates presence of the antigen in the test sample.
  • solid phases used in diagnostic immunoassays are porous and non-porous materials, latex particles, magnetic particles, microparticles (see U.S. Pat. No. 5,705,330), beads, membranes, microtiter wells and plastic tubes. The choice of solid phase material and method of labeling the antigen or antibody present in the conjugate, if desired, are determined based upon desired assay format performance characteristics.
  • the conjugate (or indicator reagent) will comprise an antibody (or perhaps anti-antibody, depending upon the assay), attached to a signal-generating compound or label.
  • This signal-generating compound or “label” is itself detectable or may be reacted with one or more additional compounds to generate a detectable product.
  • signal-generating compounds include chromogens, radioisotopes (e.g., 125I, 131I, 32P, 3H, 35S and 14C), chemiluminescent compounds (e.g., acridinium), particles (visible or fluorescent), nucleic acids, complexing agents, or catalysts such as enzymes (e.g., alkaline phosphatase, acid phosphatase, horseradish peroxidase, beta-galactosidase and ribonuclease).
  • radioisotopes e.g., 125I, 131I, 32P, 3H, 35S and 14C
  • chemiluminescent compounds e.g., acridinium
  • particles visible or fluorescent
  • nucleic acids e.g., alkaline phosphatase, acid phosphatase, horseradish peroxidase, beta-galactosidase and ribonuclease.
  • enzymes
  • chromo-, fluoro-, or lumo-genic substrate results in generation of a detectable signal.
  • Other detection systems such as time-resolved fluorescence, internal-reflection fluorescence, amplification (e.g., polymerase chain reaction) and Raman spectroscopy are also useful.
  • biological fluids which may be tested by the above immunoassays include plasma, whole blood, dried whole blood, serum, cerebrospinal fluid or aqueous or organo-aqueous extracts of tissues and cells.
  • the present invention also encompasses a method for detecting the presence of antibodies in a test sample.
  • This method comprises the steps of: (a) contacting the test sample suspected of containing antibodies with anti-antibody specific for the antibodies in the patient sample under time and conditions sufficient to allow the formation of anti-antibody/antibody complexes, wherein the anti-antibody is an antibody of the present invention which binds to an antibody in the patient sample; (b) adding a conjugate to the resulting anti-antibody/antibody complexes, the conjugate comprising an antigen (which binds to the anti-antibody) attached to a signal generating compound capable of detecting a detectable signal; and (d) detecting the presence of the antibodies which may be present in the test sample by detecting the signal generated by the signal generating compound.
  • a control or calibrator may be used which comprises antibody to the anti-antibody.
  • kits are also included within the scope of the present invention. More specifically, the present invention includes kits for determining the presence of antigens (e.g., globulomers) in a patient suspected of having Alzheimer's disease or another condition characterized by cognitive impairment.
  • a kit for determining the presence of antigens in a test sample comprises a) an antibody as defined herein or moiety thereof; and b) a conjugate comprising a second antibody (having specificity for the antigen) attached to a signal generating compound capable of generating a detectable signal.
  • the kit may also contain a control or calibrator which comprises a reagent which binds to the antigen as well as a package insert describing the procedure to be used when conducting the assay.
  • the present invention also includes a kit for detecting antibodies in a test sample.
  • the kit may comprise a) an anti-antibody specific (for example, one of the subject invention) for the antibody of interest, and b) an antigen or portion thereof as defined above.
  • a control or calibrator comprising a reagent which binds to the antigen may also be included.
  • the kit may comprise a) an anti-antibody (such as the one of the present invention) specific for the antibody and b) a conjugate comprising an antigen (e.g., globulomer) attached to a signal generating compound capable of generating a detectable signal.
  • the kit may also comprise a control of calibrator comprising a reagent which binds to the antigen as well as a package insert describing the components of the kits and how they are to be utilized.
  • the kit may also comprise one container such as vial, bottles or strip, with each container with a pre-set solid phase, and other containers containing the respective conjugates.
  • These kits may also contain vials or containers of other reagents needed for performing the assay, such as washing, processing and indicator reagents.
  • the subject invention not only includes the full length antibodies described above but also moities or fragments thereof, for example, the Fab portion thereof. Additionally, the subject invention encompasses any antibody having the same properties of the present antibodies in terms of, for example, binding specificity, structure, etc.
  • hybridoma (ML45-3C5.5; C10) which produces monoclonal antibody 3C5 was deposited with the American Type Culture Collection, 10801 University Boulevard, Manassas, Va. 20110 on Feb. 28, 2006 under the terms of the Budapest Treaty and was assigned ATCC No. PTA-7406.
  • Hybridoma (ML43-10F4.3H8) which produces monoclonal antibody 10F4 was deposited with the American Type Culture Collection, 10801 University Boulevard, Manassas, Va. 20110 on Aug. 16, 2006 under the terms of the Budapest Treaty and was assigned ATCC No. PTA-7808.
  • the A ⁇ (12-42) synthetic peptide (AnaSpec Inc.; Lot # 40443) was suspended in 100% (v/v) 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) at 40 mg/mL (5 mg in 125 ⁇ L HFIP) and incubated for complete solubilization under shaking at 37° C. for 1 h.
  • the HFIP acts as a hydrogen-bond breaker and is used to eliminate pre-existing structural inhomogeneities in the A ⁇ peptide.
  • the supernatant of the HFIP-dissolved A ⁇ (12-42) was diluted with 6.1 mL phosphate-buffered saline (PBS) (20 mM NaH 2 PO 4 , 140 mM NaCl, pH 7.4) and 625 ⁇ L 2% (w/v) sodium dodecyl sulfate (SDS) (in H 2 O) were added (final concentration of 0.2% (w/v) SDS) and incubated for 3 h at 37° C.
  • PBS phosphate-buffered saline
  • SDS sodium dodecyl sulfate
  • the supernatant was further diluted with 15 mL PBS (20 mM NaH 2 PO 4 , 140 mM NaCl, pH 7.4) and concentrated by ultrafiltration (5 kDa cut-off) to 0.65 mL, dialysed against 20 mM NaH 2 PO 4 , 140 mM NaCl, 0.05% (w/v) SDS, pH 7.4 for 16 h at room temperature, centrifuged at 10000 g for 10 min and the supernatant comprising the A ⁇ (12-42) globulomer withdrawn. The samples were aliquoted and stored at ⁇ 80° C. until further use.
  • mice were immunized sub-cutaneous with 50 ⁇ g of A ⁇ (12-42) globulomer as described in Example I in CFA (Sigma) and boosted twice at one month intervals. Spleens were collected and spleen cells fused with mouse myeloma SP2/0 cells at 5:1 ratio by a PEG procedure. Fusion cells were plated in 96-well dishes in Azaserine/Hypoxanthine selection media at 2 ⁇ 105 cells/mL, 200 mL per well. Cells were allowed to grow to form visible colonies and supernatants assayed for A ⁇ oligomer reactivity by a direct ELISA assay. Hybridomas secreting antibodies to A ⁇ oligomers were subcloned by limiting dilution, until antibody expression appeared stable.
  • the monoclonal antibodies tested were obtained (except for 6E10) by active immunization of mice with A ⁇ (12-42) globulomer (prepared as described in Example I), followed by selection of the fused hybridoma cells.
  • the individual A ⁇ forms were applied in serial dilusions and incubated with the respective antibodies for immune reaction.
  • Results are shown in FIG. 1 .
  • the anti-A ⁇ 3 globulomer mAbs 10F4 and 3C5 have a high affinity for A ⁇ -globulomer forms such as the A ⁇ (1-42) globulomer, A ⁇ (12-42) globulomer and A ⁇ (20-42) globulomer). They discriminate other A ⁇ forms such as A ⁇ -monomers to a certain extent and do not significantly recognize A ⁇ (1-42) fibrils or sAPP ⁇ .
  • the antibodies 10F4 and 3C5 can therefore be coined ‘anti-A ⁇ globulomer antibodies’.
  • a ⁇ (1-42) (Bachem, Cat. No.: H-1368) was dissolved in 500 ⁇ L 0.1% NH 4 OH in H 2 O and agitated for 1 min at ambient temperature. The sample was centrifuged for 5 min at 10000 g. The supernatant was collected. A ⁇ (1-42) concentration in the supernatant was determined according to Bradford's method (BIO-RAD Inc. assay procedure).
  • Binding of anti-A ⁇ antibodies to A ⁇ (1-42) fibrils 40 ⁇ L of A ⁇ (1-42) fibril preparation were diluted with 160 ⁇ L of 20 mM NaH 2 PO 4 , 140 mM NaCl, 0.05% Tween 20, pH 7.4 and agitated 5 min at ambient temperature, and then the sample was centrifuged for 10 min at 10000 g. The supernatant was discarded, and the residue was resuspended in 95 ⁇ L of 20 mM NaH 2 PO 4 , 140 mM NaCl, 0.05% Tween 20, pH 7.4. Resuspension was prompted by vigorous agitation (“vortexing”). Aliquots of 10 ⁇ L of the fibril preparation were each mixed with:
  • the samples were incubated at 37° C. for 20 hours, and then centrifuged for 10 min at 10000 g.
  • the supernatants were collected and mixed with 20 ⁇ L of SDS-PAGE sample buffer.
  • the residues were mixed with 50 ⁇ L of 20 mM NaH 2 PO 4 , 140 mM NaCl, 0.025% Tween 20, pH 7.4 and resuspended by “vortexing”.
  • the samples were centrifuged for 10 min at 10000 g.
  • the supernatants were discarded, and the residues were mixed with 20 ⁇ L 20 mM NaH 2 PO 4 , 140 mM NaCl, 0.025% Tween 20, pH 7.4, then with 20 ⁇ L of SDS-PAGE sample buffer.
  • the samples were applied to a 4-20% Tris/glycine gel for electrophoresis.
  • Results are shown in FIG. 3 .
  • a ⁇ (1-42) fibrils antibody heavy chain, antibody light chain and A ⁇ (1-42) monomers are marked at the edge of the gel. Due to their size, A ⁇ (1-42) fibrils cannot enter the SDS-PAGE gel and can be seen in the gel slot.
  • the relative binding to fibril type A ⁇ was evaluated from SDS-PAGE analysis by measuring the Optical Density (OD) values from the Heavy Chain of the antibodies in the fibril bound (pellet-fraction) and the supernatant fractions after centrifugation.
  • Antibodies that have bound to the A ⁇ fibrils should be co-pelleted with the A ⁇ -fibrils and therefore are found in the pellet fraction whereas non-A ⁇ -fibril bound (free) antibodies are found in the supernatant.
  • Results are shown in FIG. 3 .
  • the A ⁇ globulomer antibodies 3C5 and 10F4 bind to A ⁇ (1-42)-fibrils with a lower affinity in a co-pelleting experiment.
  • the 3C5 and 10F4 antibodies after an incubation with A ⁇ (1-42) fibrils, remain mainly after a pelleting step in the supernatant and are not co-pelleted due to being bound to the A ⁇ (1-42) fibrils.
  • the A ⁇ fibrils are a major component of the total A ⁇ peptide pool.
  • the risk of negative side effects is elevated due to a liberation of high amounts of A ⁇ which subsequently may increase the risk of microhaemorrhages.
  • An increased risk for microhemorrhages was observed in an active immunization approach with fibrillar aggregates of the A ⁇ peptide (Bennett and Holtzman, 2005, Neurology, 64, 10-12; Orgogozo J, Neurology, 2003, 61, 46-54; Schenk et al., 2004, Curr Opin Immunol, 16, 599-606).
  • Antibodies 10F4 and 3C5 show reduced staining to fibrillar A ⁇ peptide deposits suggesting that their therapeutic effect is mediated by binding to soluble globulomeric forms rather than fibrillar deposited forms of A ⁇ peptide. Since antibody binding to fibrillar A ⁇ peptide can lead to fast dissolution of aggregates and a subsequent increase of soluble A ⁇ concentration, which in turn is thought to be neurotoxic and could lead to microhemorrhages, an antibody therapy that effects the soluble globulomer rather than the monomer is preferred.
  • cortical tissue from 2 AD patients RZ16 and RZ 55
  • cortical tissue from 19 month old Tg2576 mice APPSWE #001349, Taconic, Hudson, N.Y., USA
  • 12 month old APP/L mice ReMYND, Leuven, Belgium
  • mice overexpress human APP with a familial Alzheimer's disease mutation and form ⁇ -amyloid deposits in the brain parenchyma at about 11 months of age and ⁇ -amyloid deposits in larger cerebral vessels at about 18 months of age.
  • the animals were deeply anaesthetized and transcardially perfused with 0.1 M phosphate-buffered saline (PBS) to flush the blood.
  • PBS phosphate-buffered saline
  • the brain was removed from the cranium and divided longitudinally.
  • One hemisphere of the brain was shock-frozen and the other fixated by immersion into 4% paraformaldehyde.
  • the immersion-fixated hemisphere was cryoprotected by soaking in 30% sucrose in PBS and mounted on a freezing microtome.
  • the entire forebrain was cut into 40 ⁇ m transverse sections which were collected in PBS and used for the subsequent staining procedure.
  • the neocortex samples from Alzheimer's disease patients were obtained from Brain-Net, Kunststoff, Germany as frozen tissue, immersion-fixated in 4% paraformaldehyde during thawing, and subsequently treated like the mouse tissue.
  • Staining was performed by incubating the sections with a solution containing 0.07-0.7 ⁇ g/ml of the respective antibody in accordance with the following protocol:
  • amyloid staining was additionally quantified by optically excising 10 randomly selected plaques from the histological images using the ImagePro 5.0 image analysis system and determining their average greyscale value. Optical density values (were calculated from the greyscale values by subtracting the mean background density of the stained material from the density of amyloid plaques (0%—no plaque staining above surrounding background, 100%—no transmission/maximal staining). The differences between antibodies 6E10/4G8 and 6G1, 10F4 and 3C5, respectively, were tested for statistical significance with ANOVA.
  • Antibodies 10F4 and 3C5 bind less to amyloid deposits than antibodies which recognize A ⁇ monomer or part of the A ⁇ sequence. Treatment with antibodies binding to fibrillar A ⁇ peptide can lead to fast dissolution of amyloid plaques in brain tissue and a subsequent increase of soluble A ⁇ concentration, which in turn is thought to be neurotoxic and could lead to microhemorrhages, and/or a fast dissolution of vascular amyloid, which also could lead to microhemorrhages. Therefore, an antibody therapy that effects the soluble globulomer rather than the monomer is preferred.
  • IP Immunoprecipitation
  • Sheep anti-Mouse IgG (Invitrogen Inc., Cat. no.: 112.02) is covalently bound to magnetic beads (Dynabeads).
  • the residual supernatant was thoroughly removed after the final washing step.
  • the A ⁇ peptides and the corresponding antibody were removed from the Dynabeads by adding 25 ⁇ L sample buffer without ⁇ -Mercaptoethanol (0.36 M Bistris, 0.16 M Bicine, 1% SDS (w/v), 15% (w/v) sucrose, 0.004% (w/v) Bromphenolblue) to the Eppendorff tube and heating for 5 min at 95° C. in a heating block. After cooling to room temperature the dynabeads were immobilized at the side of the reaction vial with a magnetic separator stand (MSS) and the supernatant were transferred to another Eppendorff tube (IP eluate).
  • MSS magnetic separator stand
  • a ⁇ 1-40 and A ⁇ 1-42 species were performed by a 8 M Urea Poly-Acrylamide-Gel-Electrophoresis system and subsequent Western Blot analysis according to the procedure first described by H. W. Klafki et al., Analytical Biochemistry 237., 24-29 (1996) and later also used by J. Wiltfang et al., J. of Neurochemistry 81, 481-496, 2002. There were only two minor changes made in the experimental procedure:
  • Blotting buffer 6 g Tris; 28.1 g Glycin; 500 mL Methanol; adjust to 2.5 l with water.
  • the Nitrocellulose blot was boiled for 10 min in PBS at 100° C.
  • the blot was saturated by treatment with 50 mL 5% (w/v) BSA in PBST for 1 hour at RT.
  • After removal of the fluid phase the following washing step were performed twice with: 50 mL TTBS (25 mM Tris/HCl; 150 mM NaCl Puffer; 0.05% Tween 20; pH 7.5) for 10 min at RT and subsequently with 50 mL TBS (25 mM Tris/HCl; 150 mM NaCl buffer; pH 7.5) for 10 min at RT.
  • the blot was incubated with Antibody solution II (1:10000 dilution of anti-Mouse-POD in 15 mL 3% (w/v) skimmed milk powder in 15 mL TBS) for 1 hour at RT. Removal of buffer was followed by the three wash steps as described above.
  • the anti-globulomer antibodies 10F4 and 3C5 of the present invention have a lower affinity for A ⁇ (1-42) peptide and A ⁇ (1-40) peptide in the CSF of an Alzheimer's disease patient, in comparison to the commercially available antibody 6E10 (which is, in the literature, regarded to recognize all A ⁇ -forms regardless of their conformation).
  • CSF A ⁇ -peptide forms undergo a high turnover rate (Bateman et al., Nature Medicine, 2006, 12(7):856-61) and are therefore unlikely the disease relevant species. Therefore, the CSF A ⁇ -forms should not be targeted in a passive immunization treatment strategy of Alzheimer's disease in order to reduce the risk of undesired side effects.

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